The Scientific Observer Issue 34

Pharma's Push To Resume In-Person Work Carries Consequences Improving Cancer Patient Care With Professor Mark Lawler ISSUE 34, FEBRUARY 2024 2 CONTENT FROM THE NEWSROOM 04 ARTICLE Helping Immune Cells Fight Cancer 06 Andy Tay, PhD ARTICLE Improving Cancer Patient Care With Professor Mark Lawler 09 Kate Harrison, PhD FEATURE ARTICLE Pioneering Immuno-Oncology Through a Love of Science 13 Joanna Owens, PhD ARTICLE Pharma's Push To Resume In-Person Work Carries Consequences 18 Michael S. Kinch, PhD ARTICLE Artificial Sweeteners: The Good and the Bad 21 Leo Bear-McGuinness ARTICLE What We Know – And Don’t Know – About PCOS 24 Molly Campbell 09 18 13 FEATURE Pioneering Immuno-Oncology Through a Love of Science Joanna Owens, PhD iStock 3 Kate Harrison, PhD Dr. Kate Harrison is a Senior Science Writer for Technology Networks. 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. Andy Tay, PhD Dr. Andy Tay is a Presidential Young Professor at the National University of Singapore, where his lab is dedicated to developing innovative approaches for cancer immunotherapy. Joanna Owens, PhD Dr. Joanna Owens is a Freelance Writer with more than 20 years’ experience covering a broad range of topics in biosciences, pharmaceuticals and biotechnology. Leo Bear-McGuinness Leo Bear-McGuinness is a Science Writer for Technology Networks. Michael S. Kinch, PhD Professor Michael S. Kinch is Dean of Science, Vice President for Innovation and Director of the Centers for Research Innovation in Biotechnology and Drug Discovery at Long Island University. Molly Campbell Molly is a Senior Science Writer for Technology Networks. Dear Readers, Welcome to the latest issue of The Scientific Observer magazine, and the first of 2024. At the core of this issue is a deep dive into the intricate world of cancer and the immune system. Our feature article, Pioneering Immuno-Oncology Through a Love of Science, profiles Dr. Sangeeta Goswami, a physician-scientist who felt called to a hybrid career in research after encountering many diseases that lack a definitive cure. Now, she stands at the forefront of immunotherapy research and champions young doctors – especially women – eager to pursue similar paths. In Helping Immune Cells Fight Cancer, Dr. Andy Tay explores cutting-edge strategies and recent breakthroughs in cancer immunotherapy. How are researchers removing the physical and biochemical barriers that prevent immune cells from “performing their magic” in cancer? Beyond the realm of cancer and immunology, What We Know – And Don’t Know – About PCOS offers valuable insights into the research landscape for a prevalent, yet often misunderstood, health condition. Also in this issue, Michael S. Kinch offers a thought-provoking opinion on the repercussions of big pharma companies urging their employees to return to in-person work. His opinion article explores the potential implications of this industry-wide shift and its impact on the future of work in the pharmaceutical sector. This, and much more, in issue 34. We hope you enjoy reading. The Technology Networks Editorial Team 4 FROM THE NEWSROOM From the Newsroom Want to learn more? Check out the Technology Networks newsroom. iStock, National Cancer Institute/Unsplash Ancient viral remnants buried in the genome contribute to a “smooth transition” in mouse embryonic development. JOURNAL: Science Advances. Virus Guides Embryo Development After Infecting Primitive Organisms Millions of Years Ago MOLLY CAMPBELL A traditional African psychedelic drug reduced symptoms of veterans’ brain injury in a small clinical study. JOURNAL: Nature Medicine. African Psychedelic Ibogaine Reduces Veterans’ Brain Injury Symptoms in Small Trial RUAIRI J MACKENZIE No cervical cancer cases have been observed in fully vaccinated women who received the human papillomavirus (HPV) vaccine at age 12 or 13 in Scotland since the program began in 2008. JOURNAL: Journal of the National Cancer Institute. No Cervical Cancer Cases Following HPV Vaccination in Scotland SARAH WHELAN, PHD 5 FROM THE NEWSROOM 5 Want to learn more? Check out theTechnology Networks newsroom. Georgia Institute of Technology, Gil Ndjouwou /Unplash, Braydon Anderson/Unsplash In a dramatic step away from traditional silicon-based electronics, researchers have successfully created the first functional graphene semiconductor. JOURNAL: Nature. Researchers Create World’s First Functional Semiconductor Made From Graphene ALEX BEADLE By growing the vegetables in soilless nutrient solutions, chard, arugula, radishes and peas can all be infused with or sapped of essential elements, say researchers. JOURNAL: Te Journal of the Science of Food and Agriculture. New Potassium-Poor Veg Could Benefit People With Kidney Disease, Say Researchers LEO BEAR-MCGUINNESS Researchers discovered that the development of color-sensing cells in human retinas is orchestrated by retinoic acid, an offshoot of vitamin A. JOURNAL: PLOS Bio. Vitamin A Metabolite Explains Why Humans See Colors Dogs Can’t RHIANNA-LILY SMITH 6 REMOVE PHYSICAL AND BIOCHEMICAL BARRIERS TO HELP IMMUNE CELLS PERFORM THEIR MAGIC. Our understanding of cancer, in particular, solid tumors, has improved tremendously. Since the synthesis of monoclonal antibodies in 1975, we have developed a plethora of immune checkpoint inhibitors using monoclonal antibodies (mAbs) for cancer treatment. However, mAbs have poor biodistribution in the body and do not work when there is mutational escape by cancer cells, necessitating a more advanced form of cancer immunotherapy. In 1988, Dr. Steven Rosenberg used tumor-infiltrating lymphocytes (TILs) to treat melanoma. A year later, the first generation of Chimeric Antigen Receptor T (CAR T) cell was constructed. There are now six US Food and Drug Administration (FDA)-approved CAR T-cell products in the market for cancer treatment, and as of January 2024, more than 950 registered clinical trials on ClinicalTrials. gov; the majority (93%) focusing on autologous CAR T-cell products. Despite the promise of TIL and CAR T-cell therapy, major challenges exist in using them to treat solid tumors, due to poor infiltration of immune cells into solid tumors. Here, immune cells would refer to clinically beneficial immune cell types including CD4+ helper and CD8+ cytotoxic T cells. Even after immune cells are able to infiltrate into solid tumors, the harsh tumor microenvironment, including low glucose levels, hypoxia and low pH, suppresses the functions of therapeutic immune cells. Here, we will try to understand how these obstacles reduce the efficacy of cellbased cancer immunotherapy and strategies to overcome them. OVERCOMING THE EXTRACELLULAR MATRIX The immune landscape in solid tumors can be broadly classified into inflamed, immune excluded and immune desert, based on spatial distribution of CD8+ T cells in the tumor microenvironment. An example of an immune desert or immune excluded cancer is pancreatic ductal adenocarcinoma (PDAC). Helping Immune Cells Fight Cancer ANDY TAY, PhD iStock 7 Immune desert refers to a state where CD8+ T cells are absent from the tumor and its periphery, whereas immune excluded refers to a state where there are CD8+ T cells accumulating but insufficient infiltration into tumors. One of the major factors causing this is the thick extracellular matrix surrounding solid tumors. The matrix is composed of proteins such as collagen secreted by cancer-associated fibroblasts (CAFs). McAndrews at el. found that there is significant heterogeneity of CAFs in PDAC. Fibroblast activation protein (FAP)+ CAFs were found to be tumor promoting, and their depletion enhanced survival in mouse PDAC model. On the other hand, alpha smooth muscle actin (αSMA)+ CAFs were found to be tumor restraining. This recent finding suggests that inhibition of FAP+ CAFs is a useful therapeutic target to reduce collagen secretion and extracellular matrix barrier to enhance CD8+ T cell infiltration into solid tumors. ALTERING METABOLIC STATES OF THE TUMOR MICROENVIRONMENT Even when CD8+ T cells are able to infiltrate into solid tumors, their biological activities can be suppressed due to poor availability of nutrients, low pH and oxygen levels. Immunometabolism cancer therapy is emerging as a promising paradigm to regulate immune cell fates and potentiate their anti-tumor immunity. It disrupts cancer metabolic signaling pathways such as glycolysis, tricarboxylic acid cycle and amino acid metabolism to reverse the immunosuppressive tumor microenvironment. Adenosine metabolism, in particular, has been found to play an important role in facilitating tumor immune surveillance escape, and promoting cancer progression and metastasis via restraining immune effector cell infiltration and cytotoxicity. It is known that tumors coopt the CD73/adenosine system as a mechanism for promoting tumor growth and progression, angiogenesis and immune escape. Some strategies to manipulate adenosine metabolism include encapsulating pharmacological inhibitors, monoclonal antibodies, siRNA and even CRISPR/cas9 to inhibit or shut down the activities of CD73. Importantly, as adenosine metabolism can also occur via CD73-independent pathways, it will be more beneficial to therapeutically combine CD73 inhibition with other adenosine-associated metabolic pathways to comprehensively disrupt the adenosinergic axis in cancer metabolism. THE ROAD AHEAD A recent announcement by the FDA, mandating CAR T-cell manufacturers to add a general boxed warning of potential T-cell malignancies, has caused a temporary shock to the CAR T field. In an earlier statement published in November 2023, the FDA said that “although the overall benefits of these products continue to outweigh their potential risks for their approved uses, FDA is investigating the identified risk of T-cell malignancy with serious outcomes, including hospitalization and death, and is evaluating the need for regulatory action.” A comment piece, published in Nature Medicine by Levine et al., stated that existing data suggests that CAR T-cell therapy has a low risk of secondary malignancies compared to other cancer treatments. The use of immune cells for cancer therapy is showing no signs of slowing down. Besides CD4+ and CD8+ T cells, other immune cell types including macrophages and natural killer cells are being engineered with CAR constructs for cancer treatment. Each of these cell types have their distinct advantages and may be arguably suited for different cancer types. For instance, the use of CAR macrophages, which are highly prevalent in tumors, to treat cancers that are classified as immune desert. Taking a step back, besides T cell infiltration and metabolism, innovations are also necessary to manufacture T cells that proliferate fast while maintaining their critical biological attributes to reduce costs and delays, and to deliver immune cell therapies to cancer patients who need them the most. ⚫ iStock 8 iStock Advances in cell and gene therapies are transforming the way we treat disease and injury. Join us for the second annual Cell and Gene Therapy online symposium, where expert speakers will discuss the current therapeutic landscape, covering ground-breaking research in cancer immunotherapy, vaccines, stem cells and vectors. REGISTER NOW Brought to you by the publication March 20–21, 2024 8AM PST | 11AM EST | 4PM GMT SPEAKERS Daryl Cole, PhD Sartorius John Counsell, PhD University College London Katherine Arline SHEPHERD Therapeutics Lore Gruenbaum, PhD The Leukemia and Lymphoma Society Ivana Barbaric, DPhil University of Sheffield TECHNOLOGY SPOTLIGHT SPONSORS STANDARD SPONSORS Cell and Gene Therapy ONLINE SYMPOSIUM MORE SPEAKERS TO BE ANNOUNCED SOON! 9 iStock Mark Lawler, professor of digital health, is a leader in cancer research with a focus on using the latest molecular advances and precision medicine approaches to improve patient care and address cancer inequalities on a global scale. Lawler was invited to answer your questions about precision medicine and cancer research in Technology Networks’ Ask Me Anything session. Kate Harrison (KH): What do you see as the future of tumor genomic profiling? Mark Lawler (ML): It's a really exciting area of research. This technology allows us to do things that we wouldn't have even thought of being able to do a decade ago. Not only in terms of looking at the overall constitution of the tumor from the genomics point of view, but also being able to look at single cells. Tumor genomic profiling has increased our understanding of different forms of cancer. But how do we practically translate this into companion diagnostic biomarker testing? One of the things we've been pushing for at a European level is to embed that genomic testing into the clinical setting. We propose that everybody is tested for their genomic profiles, so we can then decide the best treatment for each individual patient. The critical thing is knowing how to implement this precision oncology approach. We're great at doing the discovery part, but maybe not so good at the follow-through. KH: How do you think the potential of precision oncology can be realized more fully? ML: We've had the likes of Gleevec (imatinib mesylate) in chronic myeloid leukemia and Herceptin in HER 2-positive breast cancer. They're good examples of precision oncology working, but we probably haven't seen as many successes as we would have expected. It is important that we don't base all our hopes on precision medicine and precision oncology. Surgery and radiotherapy still cure more cancer patients than precision medicine at the moment. Improving Cancer Patient Care With Professor Mark Lawler KATE HARRISON, PhD 10 Technology Networks, adapted from Spatial Transcriptomics in Cancer. What we want to see is that precision medicine goes into radiotherapy and surgery, so that we have precision radiotherapy and precision surgery. I certainly don't think that precision oncology is going to replace either surgery or radiotherapy, but we need to be clever in terms of how we combine them. We've seen, for example, that immunotherapy and radiotherapy are a very good combination in certain tumor types. I'm very optimistic about precision oncology, but I think we need to be very realistic as well – this is not going to be the panacea that will cure all ills. It's about looking at how we use it most effectively, how we combine it with approaches that we have shown work well. For example, advances in precision radiotherapy allow for a more precise approach that targets the tumor and doesn’t damage the surrounding tissue. We also need to use companion diagnostics in the R&D process so that we can identify the patients who will benefit from treatments KH: Do you think that it will be possible to design an anti-cancer drug with 100% specificity for cancer cells only? ML: One of the challenges is moving from an approach where we understand and treat cancers individually. Immunotherapy has changed that paradigm, moving towards immunotherapy clinics, rather than colorectal cancer clinics or breast cancer clinics. Spatial transcriptomics is going to build up an atlas of what's happening in the individual cancer cell, its interactions with other cancer cells and also with the microenvironment around it. Providing an approach that is off-theshelf for everybody would be a superb vision and reality. Then, we would start to look at having cancer as a chronic disease that we can manage. Quality of life is becoming much more important as there are more people living with and beyond cancer. So, we need to be thinking not simply about cure or no cure, but more about how we manage cancer and reintegrate people into society. KH: Have there been any significant insights on the relationship between COVID-19 and cancer? ML: I’m the scientific director of DATA-CAN, which is the UK’s health data research hub for cancer. We had only just set up when the COVID-19 pandemic happened, so we rapidly repurposed our Figure 1: Several components interact with a tumor to form the tumor microenvironment. Tumor genomic profiling has increased our understanding of different forms of cancer. But how do we practically translate this into companion diagnostic biomarker testing? 11 data science work to see what the impact was. We decided to look at two things: the diagnostic pathway and the treatment pathway. For diagnostics, we looked at what's called “two-week waits” in England or “red f lag referrals” in Northern Ireland. We found that 7 out of 10 people who had a suspicion of cancer were not being referred to a specialist service. Similarly, with the treatment pathway, we looked at chemotherapy appointment attendance and found that 4 in 10 cancer patients were not attending. That data scared us so much that we immediately shared it and set up a specialist European network. We developed a 7-point plan concerning the impact of COVID-19 on cancer patients and cancer services, and we also decided to do a Pan-European study. We found that 100 million screening tests were missed during the pandemic and 1 million cancer diagnoses may have been missed. As a result, we've seen a tremendous impact on cancer patients presenting later with more aggressive disease because they were missed at that earlier stage during the pandemic. In addition to the effect of services being shut down or compromised in some way, there's also the impact of having to deal with COVID-19 when you're immunocompromised. So, cancer patients and services have suffered significantly from the pandemic. In cases such as colorectal cancer, five-year survival had improved over the last 10–20 years, but now we may have set back that progress by almost a decade, unfortunately. KH: How can diagnostic labs in low-income countries approach cancer genomics? ML: We did a Lancet series in relation to pathology and laboratory medicine in low- and middle-income countries and how to make sure that we can deliver diagnostics that are practical, that are pragmatic, and that allow delivery at a regional or national level. What we don't want to do is have that divide where low- to middle-income countries don't get access to these approaches. There are costs associated with it, so we can look at ways in which we do cost sharing, for example. I think it's the responsibility of Europe and America, for example, to support cancer research and cancer care in low- and middle-income countries, so I think we should be looking at better ways to do that. We shouldn't forget our global responsibility. Throughout the US and Europe, we are powerhouses in cancer research and its translation to cancer care. But we shouldn't be just thinking inwardly, we should be thinking outwardly and how we can support low- and middle-income countries in diagnostic approaches, therapeutic approaches, and deliver for the patients. If you're in Canada, and you're a kid with childhood leukemia, you have a 9 out of 10 chance of being alive in 5 years. If you live in Zimbabwe, that drops to a 1 in 10 chance. We are talking about treatments that are off patents, mostly chemotherapy approaches. These are curable diseases, and yet we have that disparity between the higher-income countries and low- and middle-income countries. By 2040, over 60% of deaths from cancer will happen in low- and middle-income countries, so we have a global responsibility to address that. ⚫ Mark Lawler was speaking to Kate Harrison, Senior Science Writer for Technology Networks. Edited by Lucy Lawrence and Kate Harrison. Watch this Ask Me Anything session with Professor Mark Lawler, where he answers your questions about precision medicine and cancer research. CANCER RESEARCH ANYTHING: WATCH ON DEMAND NOW Giving talks and posters at conferences can be great but can also be expensive and time consuming. Your reach is also limited to the people in the room. What if you could get your paper in front of 250,000 scientists located across the globe, without leaving your desk, for free and with minimal work? Sound too good to be true? Find out more NEED TO DISSEMINATE YOUR RESEARCH? We want to help connect scientists with great research and have created an easyto-complete form and guidance to help distil the essence of your paper into a short, punchy article that will then be shared: on our site, which receives over 1 million page views every month with our 4 million + social media followers in our 18 newsletters and may be included in our regular digital magazine The Scientific Observer iStock edited 14 S angeeta Goswami is one of a relatively rare breed – a physician-scientist, a medically qualified researcher who balances her role as a physician treating patients with a research career in the laboratory. Physician-scientists are uniquely placed to identify and then address some of the most pressing priorities in biomedical research, but it’s a journey that requires sacrifices and resilience to make it for the long haul. Goswami’s own journey began in Assam, India. Her initial fascination with science was inspired by her grandfather who was a biochemist working in academia. This ingrained a love for science at a very early age and, coupled with an inherent curiosity about the world, made studying medicine a natural choice. “India is a very densely populated country and, training in a tertiary medical center, I saw a large volume of patients,” she explains. “It was a privilege taking care of them, and something I knew I wanted to do for the rest of my life. But increasingly, I was struck by the lack of definitive curative medicines for most of the diseases we treat, and that’s where my interest in research began, when I first thought about doing a PhD.” BECOMING A CLINICIAN-SCIENTIST Goswami was the only one in a class of 160 students who decided to pursue a PhD. As there was no integrated MD-PhD program in India, she began by working on a year-long collaborative project between a Council of Scientific & Industrial Research (CSIR) laboratory and the All India Institute of Medical Sciences in Delhi. The experience confirmed her gut feeling – she wanted to delve into research in the next stage of her career. Goswami applied for PhD studentships in the United States and was accepted at Baylor College of Medicine in the Department of Immunology. Combining medical training with research is not an easy decision. “It’s a long road and it takes a lot from your life,” Goswami says. Not only is the medical training itself lengthy, but you are also adding on a separate degree or separate training to hone your research skills. As a junior investigator, it's a significant time commitment. “Sometimes, you feel you're in no man's land between two different communities – with your physician and basic science researcher counterparts having particular expectations of you,” Goswami describes. The clinical training comes first, she emphasizes. Patient care is paramount, so there can never be any compromise on your clinical skillset. At Baylor College of Medicine, she was mentored by physician-scientists Dr. Farrah K heradmand and Dr. David B. Corry, which not only opened her eyes into the field of clinical medicine and discovery science, but also marked the beginning of a passion for immunology. “The immune system is always fascinating. It’s such a finely tuned system, it’s like the porridge in Goldilocks – it can be neither too hot nor too cold. If it gets too hot, you get autoimmune disease. It's too cold, you get infections and cancer,” says Goswami. “The nuances of the immune system and how it balances all that different pathophysiology has always been fascinating to me.” Modulating the immune system has been an important goal in many complex diseases for decades, but the development of immune checkpoint inhibitors (drugs that take the brakes off the immune system) and advances in single-cell RNA sequencing has led to an explosion in our underHow a love of science, and frustration with a lack of curative treatments for cancer, led one researcher to the leading edge of cancer immunotherapy The University of Texas MD Anderson Cancer Center JOANNA OWENS, PhD 15 standing of the interplay between tumor-associated immune cells and cancer treatment and progression. T cells have been seen as key players because of the varied roles of cytotoxic T cells, T helper (TH) cells, and regulatory T cells (Tregs) in the immune responses within the tumor environment, but focus is now expanding to other cell types – from B cells involved in immune memory, to additional cell-killing power offered by natural killer cells, and the diverse roles myeloid cells play in the tumor-microenvironment. At the early stage of her career, Goswami could not yet know that her appreciation of the beauty of the immune system, and fundamental training in T cell biology, would lead her to work in a field that has transformed the cancer treatment landscape. THE IMPORTANCE OF TIMING Goswami completed her PhD before beginning her internal medicine residency at University of Pittsburgh Medical Center. “This is where my love for oncology began because I was undertaking training rotations through oncology wards and I felt a connection with patients going through such a difficult journey,” she recalls. The timing was such that, while she was in her residency, the first-inclass checkpoint inhibitor, ipilimumab, was approved for metastatic melanoma. “Suddenly, tumor immunology, which had been somewhat in the periphery of cancer research for decades, actually came to the forefront,” says Goswami. “I saw it as a sign: my love for immunology and my love for oncology coming together as tumor immunology. I knew this is what I wanted to do.” Goswami applied for a medical oncology fellowship and secured a position at The University of Texas MD Anderson Cancer Center, where she had the “pleasure and privilege” to work under the mentorship of Dr. Padmanee (Pam) Sharma. Sharma had been instrumental in the clinical research behind many of today’s immune checkpoint agents. “It was like a dream come true for me to learn from the best,” recalls Goswami. “From the start, Dr. Sharma gave me full scientific independence to pursue my research interests, while always being there as a mentor to guide me through and help me understand the big picture.” The opportunity also arose to work closely with Dr. James P. Allison, whose fundamental immunology research into checkpoint inhibition won the 2018 Nobel Prize in Physiology or Medicine (together with Dr. Tasuku Honjo). AUTONOMY TO ADDRESS KEY QUESTIONS Since 2018, Goswami has been a faculty member at MD Anderson in the Department of Genitourinary Medical Oncology, where she sees "I was struck by the lack of definitive curative medicines for most of the diseases we treat, and that’s where my interest in research began." The University of Texas MD Anderson Cancer Center 16 patients with kidney and bladder cancer and leads a lab conducting research. “We are trying to understand pathways of response and resistance to immune-based therapies across different tumor types,” she explained. Resistance to immunotherapy can be categorized as primary (tumor does not respond to immunotherapy), adaptive (where the tumor is recognized by the immune system, but it adapts to evade destruction) and acquired (where a tumor initially responded to immunotherapy but stopped). There are multiple, complex mechanisms behind these types of resistance – from low tumor mutational burden causing the tumor to be immunologically “cold” in the first place, to changes in the functions of the T cells that were once effective. Goswami was intrigued by how immune cells within tumors changed their state as cancer progresses. “We know that it’s not genetics that’s changing, so I wondered: are cues from the environment regulating genes that are in turn controlling the immune cells’ state?” she explains. “I had two questions: how does this change when we first give immune checkpoint therapy, and how does the altered immune cell state eventually dictate the response or resistance to immunotherapy?” To address these questions, Goswami had to study the epigenetic regulation of the immune cells – that is, how the gene activity within T cells was being altered by environmental cues around them. There are four main epigenetic mechanisms that control gene activity: the structure of chromatin, non-coding regions of the genome and chemical modification of DNA and histones (the proteins that provide structural support to DNA). As an immunologist, not an epigeneticist, this was a foray into a new field, and it taught her perseverance. “I definitely had my share of heartaches,” she recalls. “There were tears in the initial years when I was wondering, ‘am I asking the right question or not?’ and ‘Is it worthwhile?’, when everyone was publishing and I was at the stage where my first experiment was not working.” But Goswami did persevere, and it paid off. She discovered that patients receiving immune checkpoint therapy, especially anti-CTLA4, had increased levels of an epigenetic enzyme called EZH2 in T cells. When Goswami’s lab explored this further, they found EZH2 maintains a suppressive chromatin structure in regulatory T cells – suppressing the immune response. Moreover, adding an EZH2 inhibitor alongside checkpoint inhibitors in preclinical models, improved tumor response and survival. “This is where mentorship from Dr. Sharma became so critical. Not only did she give me full independence to pursue what I wanted to do in science, but when I got to this stage, she helped me to bring the preclinical concept to the clinic,” Goswami says. “She connected me to the right people.” In collaboration with another faculty member at MD Anderson – Dr. Ana Aparicio – Goswami initiated a clinical trial combining anti-CTLA4 with an EZH1/EZH2 inhibitor in patients who are either primaryresistant or have developed acquired resistance to immune checkpoint therapy. That trial is ongoing, and Goswami is applying a similar reverse translational approach to other questions she identified as a junior investigator. This includes trying to find biomarkers to enrich patient selection for “I saw it as a sign: my love for immunology and my love for oncology coming together as tumor immunology. I knew this is what I wanted to do.” iStock 17 iStock immunotherapy – an area where researchers are already heavily in - vesting time and resources but might not be looking in the right place. “To date, studies have looked either at tumor-specific factors like tumor mutation or burden, or were only looking from the immune perspec - tive, such as PD-L1 expression or in - terferon gamma signature,” she says. “We found we need to integrate these perspectives because the immune microenvironment doesn't work in silos. And when we did, we started to find markers.” One such project is combining two biomarkers – mutational status of a chromatin modifying complex and levels of the chemokine CXCL13 – to identify patients who are likely to respond to immune checkpoint treatment. These markers are cur - rently being validated in patients taking part in immunotherapy trials, with a view to using them to stratify patients for treatment in future stud - ies. Goswami’s lab is also expanding their work to the most intractable cancers, making progress in immune profiling glioblastoma brain tumors to find novel immune targets and demonstrating that through blocking an epigenetic regulator in myeloid immune cells it becomes possible to sensitize “immunologically cold” glioblastoma cells to checkpoint inhibitors. THE NEXT CHAPTER What does Goswami want to achieve in the next chapter of her career? First, to feel she has made a difference in a patient's life through her clinical expertise and scientific research – to improve their survival or help their cancer shift from pal - liative to curative, “I want to learn from every patient. I really hope we soon get to the stage where we can do biomarker analysis upfront to initiate treatment and then have lon - gitudinal sampling, so it’s no longer a guessing game for the clinician to know which treatment will work best at different stages.” Her second aspiration is to train the next generation of physician-scien - tists in oncology, especially providing female and immigrant scientists the opportunities and mentorship she feels have benefited her own career. “In every generation, you will find a handful of people who feel driven to take this career path, and we need to identify them early so you can nurture them and protect them,” she says. Protected time away from clinical duties to allow her to carry out her research was critical, she says, and something she wishes was rolled out to more countries, “It’s simply not productive for someone to spend the first 20 years seeing pa - tients and suddenly switch 100% to become a researcher. We need better integration of MD—PhD programs into mainstream medical education worldwide, if we want to propel clin - ical research or even fundamental research forwards." Goswami wants people – especially students aspiring to be physi - cian-scientists – to understand that it’s a long journey involving sacrific - es, commitment, and perseverance. “Especially as a female, immigrant scientist. It is not an easy decision to leave your parents behind to come to a different country for the love of science,” she says. “That’s why I'm very much motivated to train the physician-scientists of the future, especially women scientists. I have a lab of seven women at this point of time, because I feel my career has been so heavily driven and inf lu - enced by women, from my mom to my mentors, who have been instrumen - tal in shaping my career. I feel that now the onus is on me to train the next generation, to train those seven brilliant women and more." ⚫ Dr. Goswami is one of the inaugural members of the James P. Allison Institute at The University of Texas MD Anderson Cancer Center where she plans to carry on her research projects to improve out - comes with immune checkpoint therapy. 18 THE FOLLOWING ARTICLE IS AN OPINION PIECE WRITTEN BY PROFESSOR MICHAEL S. KINCH. THE VIEWS AND OPINIONS EXPRESSED IN THIS ARTICLE ARE THOSE OF THE AUTHOR AND DO NOT NECESSARILY REFLECT THE OFFICIAL POSITION OF TECHNOLOGY NETWORKS. T he tech industry in general, and biotech in particular, is amidst a troubling personnel trend that could have longterm implications, both for society and its own ability to innovate. The participating organizations are likely to be culling their prospects through a campaign of unintended, but nonetheless blatant, marginalization of their female employees. Amidst the COVID-19 pandemic, a new remote working world was betatested and rapidly normalized, all within the span of a few short weeks. Even before SARS-CoV-2 compelled the need for social distancing, many media organizations had been espousing the benefits of remote work. A February 2020 article summarized studies from Gallup, Harvard and Stanford, amongst others, which emphasized positive impacts upon worker productivity (which improved 35-40%), performance (40% fewer quality defects), retention (a 12% reduction in worker loss), profitability (21% higher earnings) and improved employee engagement (as evidenced by a 41% lower rate of absenteeism). As the Spring of 2020 unfolded, remote working rapidly evolved from exotic to nearly commonplace. The flexibility conveyed by remote working not only proved lifesaving for companies, which could not otherwise safely house their workers, but imparted an upside of the increased efficiencies as had been previously expressed by the media. These efficiencies abrogated exhausting commutes, created savings from unnecessary business trips and increased overall employee morale, even in a troubling time of societal distress. CALLS TO END REMOTE WORKING Nearly three years later, the evidence for worker productivity remained. Yet, bosses were already souring on remote and even hybrid work. A study of internal managers at Microsoft concluded that 49% of hybrid worker managers “struggle to trust their employees to do their best work.” A Citrix study further bolstered evidence of management unease with Pharma's Push To Resume In-Person Work Carries Consequences MICHAEL S. KINCH, PhD iStock 19 iStock remote working, citing evidence that “half of all business leaders believe that when employees are working ‘out of sight,’ they don’t work as hard.” The problem, it seems, is not with the remote workers, but with the perceptions of these workers by their managers. Worse still, the corrective actions being taken for a problem that may (but more likely does not) exist are likely to disproportionately damage these same companies and their managers. The call to end remote working has been amplified by many of the same technology companies that enabled these cost efficiencies, including names such as Meta, Dell and ironically, Zoom itself. The pharmaceutical industry soon followed, with retrograde actions from Roche, Novartis and Pfizer. Focusing upon this latter group, let us compare the actions of two different biopharmaceutical companies. In November 2023, Novartis announced an effort to entice workers back to the office. With the opening of new office space in Montreal, the company revealed facilities with many new discussion spaces, wellness zones as well activity spaces for employees. These facilities were touted by Novartis as amongst a variety of worker conveniences, which includes cafeterias, take-home meals, medical services, lactation rooms, federal credit union, ATMs and even dry cleaning services. This benign approach contrasts sharply with one of its major competitors. That same week as Novartis’ announcement, Albert Bourla, CEO of Pfizer, abruptly announced that Pfizer’s US employees will be required to return to the workplace for an average of 2.5 days per week, an effort that would be tightly policed from January 2024. This action was applied retrospectively to (almost – more on that momentarily) all employees, including those who had historically worked remotely before the pandemic. This abrupt change might not have seemed particularly newsworthy except that Pfizer then announced the closure of multiple sites across the United States. This announcement built upon the fact that, as part of cost-cutting measures, the company had already largely curbed the ability of many employees to return to work when it shuttered or razed major office centers in Connecticut, New Jersey and Michigan. Given that the company intended to pink slip those employees failing to meet their 50% on-site requirement, the company was effectively dismissing large swathes of its workforce, which conveniently aligned with the fact that the company also announced a reduction in force of roughly one-quarter of their employees. Putting aside the business strategy captured by this series of executive decisions, let us consider the impact. According to the Washington Post, women are more likely to work remotely and a YouGov poll confirmed that women place greater importance on flexibility than their male counterparts, a fact that was confirmed by a McKinsey study of women in the workplace. Aside from the bias caused by such decisions, one might question the business sense of decisions to curtail remote working. It has been well established that greater diversity improves overall corporate performance. Evidence comes from feedback received from both hiring managers and large scale studies, which reveal that “differences in age, ethnicity, gender and other dimensions foster high performance.” Diverse teams outperform individuals by nearly 90% in terms of decision-making, and genderdiversity is particularly impactful. By potentially culling the diversity and morale of an organization by half, the long-term ramifications of innovation-dependent organizations that are eliminating remote work raises serious questions about the future. A remoteness in commonsensical thinking seems to be dominating the boardrooms of many technology companies. ⚫ 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? 21 iStock CAN SWEETNESS EVER COME WITHOUT HEALTH RISKS? S ugar makes life that little bit sweeter, but its taste can come at a calorific cost. That dusting on your cereal, that white cube in your tea – these little dashes of the sweet stuff can add up to more than just weight gain; if consumed in large enough amounts over years, sugar can contribute to serious conditions like diabetes and heart disease. It’s little wonder, then, that many consumers in recent years have ditched sugar in favor of artificial sweeteners, some of which boast zero calories. But are these fabricated flavorings really any better for us? Well, they have their good and bad qualities, according to the latest research. THE GOOD Many people opt for artificial sweeteners to help them lose weight, and there is some research to show that the sweeteners can help shift the pounds. One study found that young adults who replaced their regular soft drink with a sugar-free version lowered their body mass indexes (BMIs) by 1.3–1.7 points, on average. A meta-analysis of 15 randomized controlled clinical trials also concluded that low-calorie sweeteners are associated with modest decreases in body weight and fat mass. Other sweetener-obesity studies, however, have come to different conclusions, but we’ll come to that research later… As for other benefits, one 2018 study found that the sweetener saccharin has a strong affinity for a protein associated with aggressive cancers. At the time, the researchers said that the flavoring could one day form the basis of a more selective cancer therapy. A more recent study found that, in test tube experiments, a novel artificial sweetener increased the levels of beneficial human gut microbes such as Bifidobacterium and Lactobacillus. And when it comes to sustainability, some artificial sweeteners may just have the advantage. A study published last year found that stevia sweeteners Artificial Sweeteners: The Good and the Bad LEO BEAR-MCGUINNESS 22 iStock produce around 10% of the greenhouse gas emissions of sugar. THE BAD While most health authorities consider sweeteners, on the whole, safe to consume, recent research has highlighted some of the flavorings’ unsavory effects. Many studies have linked the sweeteners to a higher risk of cancer, for instance. One recent paper found that survey participants who consumed larger amounts of aspartame and acesulfame-K had an increased overall risk of cancer compared to non-consumers. These kind of findings led the World Health Organization (WHO) to infamously list aspartame as a “possible carcinogen” last July. Other studies have observed a link between the sweeteners and an increased risk of cardiovascular diseases. One paper, published last year in Nature Medicine, observed that patients who had experienced heart attacks and strokes were more likely to have elevated levels of the sweetener erythritol in their blood. After experimenting with the flavoring in the lab, the researchers seemingly proved that the sweetener did make human platelets easier to activate and clot, fostering “enhanced thrombosis.” When it comes to behavioral effects, several studies have linked sweeteners to nervousness. One experimental study published last year found that aspartame produced anxiety-like behavior in mice. “We believe that aspartame produces a shift in the excitation-inhibition balance, in favor of excitation,” Pradeep Bhide, Chair of Developmental Neuroscience at Florida State University College of Medicine, told Technology Networks at the time. And as for obesity, while several trials have linked use of the sweeteners to modest decreases in body weight and fat mass, other studies have found the opposite effect. One paper published in 2016 found that that artificial sweeteners mimic a starvation state in the brains of fruit flies, causing them to seek energy by eating more food. This kind of contrary research led the WHO to take a fairly neutral stance on the sweeteners’ dietary benefits last year. After accepting recommendations of a recent systematic review of the research, the health organization said that use of the sweeteners “does not confer any long-term benefit in reducing body fat in adults or children.” “People need to consider other ways to reduce free sugars intake, such as consuming food with naturally occurring sugars, like fruit, or unsweetened food and beverages,” Francesco Branca, WHO Director for Nutrition and Food Safety, said in a statement last May. “NSS [non-sugar sweeteners] are not essential dietary factors and have no nutritional value. People should reduce the sweetness of the diet altogether, starting early in life, to improve their health.” CONCLUSION So, are artificial sweeteners good or bad for us? Well, if successfully used to wean a person off high-calorie, sugary treats, the flavorings could incur some health benefits (albeit with possible nervousness side effects). But health authorities like the WHO aren’t convinced these benefits occur in practice. Ultimately, consumers may be best off taking the organization’s advice and limiting the sweetness in their diets altogether, as difficult as that may be. ⚫ 1863 An inflammatory link? Rudolf Virchow observed the connection between cancers and inflammation. He noted that some tumors are often associated with immune cells, and that chronic inflammation predisposes cancer development. What is cancer immunology? The cancer immunology timeline 1902 Cell therapy attempted Physicians Ferdinand Blumenthal and Ernst von Leyden attempt the first form of cell therapy for cancer. They endeavor to vaccinate patients against their cancer using their own tumor cells. Two patients experience subjective improvements, but there were no significant reductions in tumor size. 1981 First preventative vaccine The hepatitis B vaccine becomes the first FDA-approved vaccine for cancer prevention. The vaccine prevents liver cancer caused by chronic infection from the hepatitis B virus. 2015 Oncolytic viruses The first oncolytic virus, talimogene laherparepvec (T-VEC), is approved by the FDA for the treatment of inoperable metastatic melanoma. T-VEC is a genetically modified herpes virus that infects and kills cancer cells after injection into the tumor. It also produces the cytokine granulotyctemacrophage colony-stimulating factor (GM-CSF) that promotes the development of immune cells. 2018 Nobel Prize awarded The Nobel Prize in Physiology or Medicine is jointly awarded to James P. Allison and Tasuku Honjo in recognition of their discovery of cancer therapy by inhibition of negative immune regulation. The identification of immune checkpoint proteins CTLA-4 and programmed cell death protein 1 (PD-1) are a “landmark in our fight against cancer” and have enabled the successful development of ICIs used in the clinic today. 1909 Immunosurveillance Paul Erlich proposes the “immunosurveillance” hypothesis, suggesting the host’s immune system usually suppresses cancer formation from growths of abnormal (neoplastic) cells. He stated: “in the enormously complicated course of fetal and post-fetal development, aberrant cells become unusually common. Fortunately, in the majority of people, they remain completely latent thanks to the organism’s positive mechanisms.” 1891 Coley’s toxins William Coley, the “Father of Immunotherapy”, creates what is thought to be the first immune-based cancer treatment. He observed cancer patients achieving remission after contracting a streptococcal skin infection, which inspired him to test injecting mixtures of live and inactivated bacteria into tumors, known as “Coley’s toxins”. 1904 Viruses and cancer George Dock describes a leukemia patient achieving remission after contracting a severe influenza infection. However, the connection between viruses and cancer would not be explored in more detail until later in the 20th century. 1987 Immune checkpoints The first immune checkpoint molecule, cytotoxic T lymphocyte antigen number 4 (CTLA-4), is discovered. CTLA-4 binds to T cells and acts as a “brake”, keeping them in an inactive state. Yet, its exact function remained unclear until 1995 when James Allison and colleagues discovered its inhibitory effect on T cells and its potential as a future target for anti-cancer therapy. 1992 PD-1 immune checkpoints Tasuku Honjo and colleagues publish their discovery of immune checkpoint protein programmed death-1 (PD-1). PD-1 is a receptor expressed on the surface of activated T cells that bind to ligands PD-L1 and PD-L2 to downregulate their activity and inhibit the immune response. 2022 Further cell therapies The first T-cell receptor-based anticancer therapeutic (Tebentafusptebn) is approved by the FDA for treating metastatic uveal melanoma (cancer of the pigment-producing cells of the eye). This is a first-in-class immunemobilizing monoclonal T-cell receptor against cancer (ImmTAC), which binds to cancer cells expressing the antigen of interest and recruits T cells to kill them. In this infographic, we will explore how the cancer immunology field has advanced over time, highlighting key developments in research and therapeutics. The field of cancer immunology concerns the study of the interaction between the immune system cancer cells. These abnormal cells grow uncontrollably, forming tumors and spreading around the body. Today, therapies that help the immune system to fight cancer – immunotherapies – are considered one of the key pillars of cancer treatment alongside surgery, chemotherapy and radiotherapy. Research and modern technology have allowed us to learn more about the role of the immune system in cancer, from how it can either prevent or promote cancer development, and how we can use its anti-cancer abilities to create effective immunotherapies. What are some of the major milestones in our knowledge of the immune system and cancer? 1957 Immunosurveillance revisited The theory of cancer immunosurveillance is revisited by Lewis Thomas and Macfarlane Burnet, suggesting that cancers produce tumor-specific antigens that trigger an immune response to destroy most precursors of cancer. 1967– 1975 Viral origins revealed In 1967, Jacques Miller discovers the existence of T cells as well as their functions in immunity. Ralph M. Steinman discovers dendritic cells in 1973, as well as their role in the adaptive immune response. The activity of natural killer (NK) cells is also first described in a 1975 paper. 1915 Immune cell stimulation From experiments with mice, Rockefeller Institute physicians James B. Murphy and John J. Morton formulate their hypothesis that nonspecific stimulation of immune cells such as lymphocytes may represent a treatment for cancer. 1964 Viral origins revealed The Epstein–Barr virus (EBV) is first linked to cancer development after its discovery in Burkitt lymphoma cancer cells. EBV would later be linked to other cancers such as nasopharyngeal cancers, Hodgkin lymphoma and some gastric cancers. 1977 Immunotherapies as standard? Lloyd J. Old, pioneer of immunooncology, predicts that cancer immunotherapy will one day become standard practice alongside chemoand radiotherapy. 1990 First immunotherapy approval The live tuberculosis (TB) vaccine, Bacillus Calmette-Guerin (BCG), becomes the first approved anticancer immunotherapy. It is still used today to prevent recurrence of nonmuscle invasive bladder cancer. 1997 First monoclonal antibody therapy Rituximab becomes the first monoclonal antibody approved by the FDA for the treatment of cancer, specifically non-Hodgkin’s lymphoma. Rituximab targets and binds to the cell surface protein CD20 found on mature B cells, activating the immune system and inducing B cell death. 2011 First immune checkpoint inhibitor Ipilimumab becomes the first immune checkpoint inhibitor (ICI) to be approved by the FDA. This is an antibody drug that targets and inhibits CTLA-4, releasing the “brake” on T cells and allowing activate and attack cancer cells. 2010 First therapeutic vaccine The first (and to this date the only) therapeutic cancer vaccine – sipuleucel-T – is approved by the FDA to treat castration-resistant prostate cancer. It is an autologous dendritic cell-based vaccine, meaning it uses the patient’s own cells to generate an immune response against prostate acid phosphatase, an antigen expressed by prostate cancer cells. 2014 More ICIs approved Another ICI, and the first PD-1 inhibitor, pembrolizumab, is approved by the FDA as a second-line treatment for advanced melanoma. 2017 CAR T-cell therapy The first chimeric antigen receptor (CAR) T-cell therapy, tisagenlecleucel, is approved by the FDA. In this therapy, T cells are extracted from the patient and genetically engineered to produce receptors against their cancerous B cells. They are re-infused back into the patient where they target and kill the leukemia cells. It is approved for treating children and young people with a form of relapsed lymphoblastic leukemia. 24 iStock P olycystic ovary syndrome (PCOS) is the most common hormonal disorder in women of reproductive age. Despite affecting 8–13% of women, its diagnosis can prove challenging and typically requires a visit to 1 or more physicians over the course of at least 1 year. As a result, up to 70% of women remain undiagnosed worldwide according to the World Health Organization (WHO). PCOS can cause unpleasant symptoms and is associated with morbidities such as fertility issues, metabolic syndromes and impaired glucose tolerance. Here, we explore what researchers know – and don’t know – about PCOS and fertility. WHAT IS PCOS AND HOW IS IT DIAGNOSED? PCOS is a condition that can be characterized by elevated levels of male sex hormones, called androgens, and/or the formation of small fluid-filled sacs (cysts) on one or both ovaries, which is where the name of the disorder originates from. Understanding the cause of PCOS and diagnosing it is complex; some women develop cysts (morphological symptoms), while others present with symptoms that are biochemical in origin. The hormone imbalances present in women with PCOS affect ovulation, the process where the ovaries release an egg into the uterus. Infrequent or absent ovulation can manifest as irregular menstrual cycles or a complete lack of menstruation for some women. Individuals with PCOS are also at an increased risk of developing other health conditions, including but not limited to What We Know – And Don’t Know – About PCOS MOLLY CAMPBELL 25 iStock type 2 diabetes mellitus, high cholesterol, endometrial cancer and heart disease. The process of diagnosing PCOS is one of exclusion, where all other potential causes for the following symptoms must be ruled out: • Symptoms of high androgen levels – including the growth of unwanted facial or bodily hair, acne or elevated blood testosterone levels • Menstrual periods that are irregular or absent • Polycystic ovaries detected on an ultrasound scan Current guidelines require that a diagnosis of PCOS must be based on the presence of at least two of the above criteria. IS THERE A KNOWN CAUSE OF PCOS? PCOS is an example of a multifactorial disease, which means it can be caused by a variety of factors that may or may not influence each other. Research has demonstrated that genetic and environmental factors can contribute to a person developing PCOS, but an exact cause for the condition is not yet known. INSULIN RESISTANCE AND PCOS Insulin resistance affects 50%–70% of women with PCOS, which has led to a body of research exploring whether insulin resistance might even be the root cause of the condition. Insulin is produced when blood glucose levels rise and helps our cells take in glucose so that it can be stored for energy. Insulin resistance occurs when the body does not respond to insulin efficiently. Over time, this means that a greater amount of insulin is required for our cells to take up the same amount of glucose. Excess insulin levels – or hyperinsulinemia – can drive excessive androgen production. Increased insulin levels can also contribute to other metabolic complications that are associated with PCOS. The issue is that not every woman with PCOS also has insulin resistance, so while there might be a connection, a causal relationship has not been established. GENETIC AND EPIGENETIC INFLUENCES IN PCOS PCOS can run in families and has an estimated heritability of 70%, but how PCOS might be inherited is not well understood. Twin-, familyand population-based studies have identified genetic variants – some of which are implicated in the pathways of androgen biosynthesis – as being associated with the disorder. However, functional genomics studies that can explain the significance of identified genetic variants are currently lacking. Genetic research has also indicated that there might be several subtypes of PCOS, adding further complexity to the disorder’s pathophysiology. Dapas et al. analyzed the genes of ~900 women suffering from irregular menstrual periods. The women were categorized based on their body mass index (BMI), levels of glucose, insulin and reproductive hormones. The genetic analyses revealed two apparent subtypes of PCOS: a “reproductive group” and a “metabolic group”, with each subtype being associated with a specific group of gene variants. In the reproductive group, ~23% of women had higher levels of luteinizing hormone (LH) and sex hormone binding globulin (SHBG), in addition to a lower BMI and insulin levels. Approximately 37% of the metabolic group had lower levels of SHBG and LH, a higher BMI and higher glucose and insulin levels. “Our study provides support for the hypothesis that PCOS is in fact a heterogeneous disorder with different underlying biological mechanisms,” the authors said. “As a consequence, grouping women with PCOS under a single diagnosis may be counterproductive because distinct disease subtypes will likely benefit from different interventions.” Attention has also turned to the potential contribution of epigenetics, which regulates gene activity without causing changes to the underlying DNA sequence, in PCOS pathophysiology. In mice, excess prenatal exposure to anti-Müllerian hormone (AMH) leads to PCOS symptoms in the mother’s offspring. A 2021 study by Mimouni et al. suggests that such epigenetic mechanisms might ensure certain traits in affected mice are transmitted to future generations. Whether this transgenerational inheritance could occur in humans is not yet known. PCOS AND FERTILITY – WHAT’S THE LATEST? Research to date suggests that the complexity and heterogenic nature of PCOS 26 iStock rule out a likely single cause. A cure for the condition therefore does not exist, though pharmacological interventions – such as the contraceptive pill – and lifestyle changes can help to regulate the menstrual cycle and address other symptoms. A major concern for couples affected by PCOS is fertility; an estimated ~90–95% of anovulatory women seeking infertility treatment have the condition. “One of the main symptoms of PCOS is anovulation, which means that women will ovulate irregularly or not at all. That can make it challenging to fall pregnant naturally,” Dr. Katrina Moss, a research fellow in the School of Public Health at the University of Queensland, explained. Challenging, but not impossible; many people with PCOS do conceive naturally. For those who do not, there are several fertility treatment options available, which are typically prescribed in a stepped manner. Though care guidelines differ across the world, oral drugs that are ovulation-inducing (OIs) are often the firstline treatment for anovulatory fertility in women that do not have other infertility factors. “Patients doing OI will take medication to encourage egg development and their specialist will monitor how many follicles are developing. Once the biggest follicle reaches the desired size, patients will have a trigger injection to mature the egg and release it from the follicle. The patient will have timed intercourse or insemination to complete the process,” Moss said. Injectable gonadotropins, which also stimulate ovulation, have been used as a traditional next line of treatment. Women might then choose to explore options including intrauterine insemination (IUI) and/or in vitro fertilization (IVF). Moss recently explored the birth rates and outcomes of women with and without PCOS using data from the Australian Longitudinal Study on Women’s Health. “The Australian Longitudinal Study on Women’s Health has been collecting data from a dedicated sample of women since 1996, so it gives us a unique opportunity to understand the whole story when it comes to fertility treatment,” she explained. The study analyzed the outcomes of women with PCOS using fertility treatments according to the clinical practice guidelines adopted in Australia. These guidelines recommend a treatment plan of OI, followed by IUI and IVF. “We studied 1109 women who were using fertility treatments and found no difference in births between the women with and without PCOS or between those on different treatment paths,” Moss said. The study also found that non-invasive treatments such as OI are effective for women with PCOS; fewer women with PCOS progressed to IVF after OI compared to those without the condition. PCOS can run in families and has an estimated heritability of 70%, but how PCOS might be inherited is not well understood. 27 iStock “OI is less invasive than IVF because everything happens in the patient’s body. It’s also more affordable because there is less medical intervention required. For people with PCOS where their only barrier to falling pregnant is that they are not ovulating, OI may be all they need,” said Moss. It’s important to note that age might be a key factor for success, as the study found more women with PCOS were likely to start fertility treatments earlier (age 31) than those without (age 34). “However, if the partner also has fertility challenges, IUI or intracytoplasmic sperm injection might be needed. And patients with conditions such as endometriosis may be better off going straight to IVF as that treatment is more suited to their condition. The priority should be to get patients into the most suitable treatment for them as quickly as possible,” Moss added. The study carries limitations in that it is retrospective and that the findings might not translate to other parts of the world beyond Australia. However, Moss hopes that the team’s findings are a source of comfort: “We think that women with PCOS can stress a bit less about fertility treatment. Most won’t have fertility problems and if they do it is highly treatable. Many women with PCOS start thinking about their fertility early, which is key factor in their high birth rates,” she said. THE LANDSCAPE OF PCOS RESEARCH AND FUNDING There are many unknowns surrounding PCOS, which presents challenges for patients, clinicians and researchers alike. Adequate funding for research is a critical factor in getting answers. Brakta et al. estimated the National Institutes of Health (NIH) funding allocations for PCOS over a 10-year period (2006-2015). The study compared PCOS research funding to grants awarded for three disorders with similar degrees of morbidity and prevalence: rheumatoid arthritis (RA), tuberculosis (TB) and systemic lupus erythematosus (SLE). “PCOS, compared with RA, TB, and SLE, was relatively less funded (total mean 10- year funding was $215.12 million vs $454.39 million, $773.77 million and $609.52 million, respectively),” the authors concluded. When discussing why PCOS research might be underfunded, Brakta et al. highlight the fact that generally, diseases of women are underfunded – though efforts are being made to address this. Additionally, the fact that PCOS is a metabolic disorder, which also carries reproductive consequences, might complicate the distribution of funding resources from different institutes; to which research area should funding be appropriately allocated? A recent analysis of global trends in PCOS research suggests that the condition’s pathogenesis has become a “long-term forefront of research”. In more recent years, additional attention has been paid to health management in PCOS prevention and the potential long-term complications of the condition. With growing evidence highlighting the condition’s impact on quality of life and wellbeing, PCOS research and drug development is clearly an area of unmet need. 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