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• Published: 05 December 2019

Looking forward 25 years: the future of medicine

Nature Medicine volume  25 ,  pages 1804–1807 ( 2019 ) Cite this article

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A Publisher Correction to this article was published on 27 January 2020

This article has been updated

To celebrate the end of our 25th anniversary year, we asked thought leaders and experts in the field to answer one question: What will shape the next 25 years of medical research?

Core member and chair of the faculty, Broad Institute of MIT and Harvard; director, Klarman Cell Observatory, Broad Institute of MIT and Harvard; professor of biology, MIT; investigator, Howard Hughes Medical Institute; founding co-chair, Human Cell Atlas.

For many years, biology and disease appeared ‘too big’ to tackle on a broad level: with millions of genome variants, tens of thousands of disease-associated genes, thousands of cell types and an almost unimaginable number of ways they can combine, we had to approximate a best starting point—choose one target, guess the cell, simplify the experiment.

But we are now on the cusp of an inflection point, where the ‘bigness’ of biomedicine turns into an advantage. We are beginning to see advances towards these goals already, in polygenic risk scores, in understanding the cell and modules of action of genes through genome-wide association studies (GWAS), and in predicting the impact of combinations of interventions. Going forward, our success in harnessing bigness will rely on our ability to leverage structure, prediction and expanded data scale. Disease is highly structured at the molecular, genetic, gene program, cell and tissue levels; acknowledging and understanding this structure can help us reduce the overwhelming lists of genes and variants to a manageable number of meaningful gene modules . We cannot test every possible combination, so we need algorithms to make better computational predictions of experiments we have never performed in the lab or in clinical trials. But only when data are truly big, scaled massively and rich in content, will we have the most effective structuring and prediction power towards building a much-needed Roadmap of Disease for patients.

To achieve this, we need to invest in building the right initiatives—like the Human Cell Atlas and the International Common Disease Alliance—and in new experimental platforms: data platforms and algorithms. But we also need a broader ecosystem of partnerships in medicine that engages interaction between clinical experts and mathematicians, computer scientists and engineers who together will bring new approaches to drive experiments and algorithms to build this Roadmap.

PhD investigator, Howard Hughes Medical Institute; core member, Broad Institute of MIT and Harvard; James and Patricia Poitras Professor of Neuroscience, McGovern Institute for Brain Research, MIT.

Although it is difficult to pinpoint an exact value, it is safe to estimate that more than 250 patients have been treated with gene therapies for monogenic diseases for which there previously were no treatment options. Add in the patients who have received CAR-T therapy, and that number rises into the thousands. This is an enormous success, and it represents the beginning of a fundamental shift in medicine away from treating symptoms of disease and toward treating disease at its genetic roots.

Gene therapy has been under development for more than 30 years, but several recent major advances have tipped the scales toward clinical feasibility, including improved delivery methods and the development of robust molecular technologies for gene editing in human cells. In parallel, affordable genome sequencing has accelerated our ability to identify the genetic causes of disease. With these advances, the stage is set for the widespread use of gene therapy. Already, nearly 1,000 clinical trials testing gene therapies are ongoing, and the pace of clinical development is likely to accelerate.

To fulfil the potential of gene therapy and ensure that all patients have access to this revolutionary treatment, we will need to continue developing delivery approaches that are practical and widely usable, to refine molecular technologies for gene editing, to push our understanding of gene function in health and disease forward, and to engage with all members of society to openly discuss the risks and benefits of gene therapy.

Elizabeth Jaffee

Dana and Albert “Cubby” Broccoli Professor of Oncology, Johns Hopkins School of Medicine; deputy director, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.

“An ounce of prevention is worth a pound of cure.” Benjamin Franklin said this in reference to fire safety, but it can easily be applied to health too. The twentieth century saw amazing advances aimed at preventing the onset of disease—including vaccines and risk-factor interventions—nearly doubling life expectancy worldwide. Only two decades into the twenty-first century, healthcare has already entered its next phase of rapid advancements. By using precision medicine technologies, genetic vulnerabilities to chronic and deadly diseases at the individual level can now be identified, potentially pre-empting disease decades later.

My hope for the next 25 years is that someday a single blood test could inform individuals of the diseases they are at risk of (diabetes, cancer, heart disease, etc.) and that safe interventions will be available. I am particularly excited about the possibility of developing cancer vaccines. Vaccines targeting the causative agents of cervical and hepatocellular cancers have already proven to be effective. With these technologies and the wealth of data that will become available as precision medicine becomes more routine, new discoveries identifying the earliest genetic and inflammatory changes occurring within a cell as it transitions into a pre-cancer can be expected. With these discoveries, the opportunities to develop vaccine approaches preventing cancers development will grow.

But, as is the case today, prevention technologies can only be fully successful if they are widely available, to reduce unnecessary morbidity and mortality and healthcare costs and further raise life expectancy. Global accessibility is key to reduce global disparities. For these strategies to work, funding agencies should consider prioritizing prevention strategies.

Jeremy Farrar

Director, Wellcome Trust.

Politics, demographics, economics, climate—how the world changes and interacts fundamentally affects all of us. Research is part of that and can help provide solutions to the great challenges we face, but only if the three pillars of science, innovation and society come together in an environment where people and teams can thrive. We must therefore take the opportunity today to shape how the culture of research will develop over the next 25 years.

Building a career in research can be incredibly rewarding, yet it often comes at a cost. The drive for research excellence—to which Wellcome has certainly contributed—has created a culture that cares more about what is achieved than how it is achieved. We can do better, and building a creative, inclusive and open research culture will unleash greater discoveries with greater impact.

Changing culture requires us to acknowledge the issue and then make a long-term commitment. As an independent foundation, Wellcome is able to acknowledge the issue and make that commitment. This is a permanent shift in our thinking. Working openly with, and as part of, the wider research community, we aim to make research inclusive, more inspiring, more fun, more rewarding. As a result, it will contribute even more to making the world a healthier place to live.

John Nkengasong

Director, Africa Centres for Disease Control and Prevention.

Population wise, Africa is the continent of the future. By 2050, it is estimated that its population will be 2.5 billion people. This means that one in every four persons in the world might be an African, with rapidly growing economies and a rising middle class. These demographic changes have important implications for both communicable and noncommunicable disease patterns, including emerging and re-emerging infectious diseases; resistance to antibiotics; and rising rates of cancers, diabetes, cardiovascular diseases and maternal and child deaths. To meet its health challenges by 2050, the continent will have to be innovative in order to leapfrog toward solutions in public health.

Precision medicine will need to take center stage in a new public health order—whereby a more precise and targeted approach to screening, diagnosis, treatment and, potentially, cure is based on each patient’s unique genetic and biologic make-up. For example, universal newborn screening and a more accurate analysis of causes of death in this age group could be established to curb under-five mortality; genetic screening programs could help avoid progression towards aggressive cancers; and medicine side effects could be reduced if tests could predict negative reactions and enable caregivers to proactively prescribe alternative treatments.

In Africa, precision medicine should not be seen from the lens of sequencing whole genomes, diagnosing DNA abnormalities and developing medications targeted to very small populations. Rather, African countries should begin pursuing policy approaches and partnerships to advance precision medicine to meet the African Union’s Agenda 2063 goals. This includes the integration of precision medicine approaches into national strategies to improve healthcare—including genomic data policy—and increase diagnostic capacity, and the creation of biobanks, such as H3Africa, that encompass both physical and bioinformatics facilities.

Executive vice-president, Scripps Research Institute; founder and director, Scripps Research Translational Institute.

Twenty-five years ago, the World Wide Web was just getting off the ground. Therefore, when thinking of the medical research landscape in 25 years, it is reasonable to think big and without limits.

In 2045, I hope we will have developed a planetary health infrastructure based on deep, longitudinal, multimodal human data, ideally collected from and accessible to as many as possible of the 9+ billion people projected to then inhabit the Earth.

This infrastructure, by using hybrid artificial intelligence (AI) models—including various deep neural networks, federated AI, nearest-neighbor analysis and systems yet to be developed—could provide individualized guidance for the prevention and optimal management of medical conditions, acting as a virtual medical coach for patients and a platform for clinicians to review a patient’s real-time, real-world, extensive and cumulative dataset.

Some have projected that, by this juncture, artificial general intelligence (AGI) will have been developed, giving machines enhanced capabilities to perform functions that are not feasible now. Notwithstanding that uncertainty, it is likely that machines’ ability to ingest and process biomedical text at scale—such as the corpus of the up-to-date medical literature—will be used routinely by physicians and patients. Accordingly, the concept of a learning health system will be redefined.

Linda Partridge

Professor, Max Planck Institute for Biology of Ageing.

Human life expectancy has increased over the past 170 years in many parts of the world. Unfortunately, the healthy lifespan has not, and the period of life when a person lives with disability and illness at the end of life is growing, especially in women.

But ageing is malleable, and mounting evidence suggests that late-life ill health can be combated. In laboratory animals, including mice and rhesus monkeys, genetic, lifestyle and pharmacological interventions can increase not only the lifespan, but also the healthspan. In humans, improvements in diet and the implementation of physical exercise regimes can effect major health improvements, but better lifestyle is not enough to prevent age-related diseases.

The big hope is that 25 years from now, medical sciences will have progressed enough to enable people to have healthier and more active lives almost up until their eventual death. Going forward, the direct targeting of mechanisms of ageing, including with existing drugs, presents an opportunity to reduce disability and illness in late life. Sirolimus, an mTORC1 inhibitor, extends the lifespan of laboratory animals and in clinical trials has proved to boost the immune response of older people to vaccination against influenza. Other drugs, such as the combination of desatinib and the BCL-2 inhibitor quercetin, which kill senescent cells, are farther from the clinic but show promise. Plasma from younger mice has been shown to have a beneficial effect on the stem cell function of several tissues in older mice; work to identify the natural metabolites responsible for this effect could open up avenues for translation to the clinic. Geroprotective drugs, which target the underlying molecular mechanisms of ageing, are coming over the scientific and clinical horizons, and may help to prevent the most intractable age-related disease, dementia.

Trevor Mundel

President of Global Health, Bill & Melinda Gates Foundation.

The most essential innovations in medical research over the next 25 years won’t just come from the explorations of bench scientists or the emergence of new technologies. They will come from what we do—as partners across the public and private sectors—to forge a new applied research ecosystem dedicated to the rapid discovery, development and delivery of life-changing tools that have been designed with the end user in mind.

This will mean finding new ways to share clinical data that are as open as possible and as closed as necessary. It will mean moving beyond drug donations toward a new era of corporate social responsibility that encourages biotechnology and pharmaceutical companies to offer their best minds and their most promising platforms. And it will mean working with governments and multilateral organizations much earlier in the product life cycle to finance the introduction of new interventions and to ensure the sustainable development of the health systems that will deliver them. If we focus on these goals, we can deliver on the promise of global health equity.

Josep Tabernero

Vall d’Hebron Institute of Oncology (VHIO); president, European Society for Medical Oncology (2018–2019).

Let’s briefly skip back 25 years. In oncology, who could have predicted that the stunning advances in genome sequencing would come to shape clinical decision-making? Who could have foreseen the increasing availability of genetic patient screenings or the promise of liquid biopsy policing of disease? Very few, which is why it is a fool’s errand to make sweeping predictions. But let’s try.

Over the next 25 years, genomic-driven analysis will continue to broaden the impact of personalized medicine in healthcare globally. Precision medicine will continue to deliver its new paradigm in cancer care and reach more patients. Immunotherapy will deliver on its promise to dismantle cancer’s armory across tumor types.

I also anticipate that AI will help guide the development of individually matched therapies, the harnessing and exchange of big data, and advances in telemedicine to bring crucial medical expertise to more patients everywhere. But the prospect is not all rosy. I worry about the exacerbating burden of comorbidities in cancer patients. We must collectively seek to strengthen and unify medical fields, with particular emphasis on oncology and cardiology. This is an emerging area for collaboration. Implementation research in the prevention and control of cancer will also be critical, as will be the shaping and strengthening of cancer policy-making at the global, national and regional levels.

With continued belief that scientific endeavors should be prioritized to respond to society’s and citizens’ needs, the scientific community must grasp future opportunities to uphold the very ethos of medicine as we continue to push boundaries in discovering new ways to extend and improve patients’ lives.

Pardis Sabeti

Professor, Harvard University & Harvard T.H. Chan School of Public Health and Broad Institute of MIT and Harvard; investigator, Howard Hughes Medical Institute.

A cataclysmic global pandemic is one of the greatest risks to humanity. Over the last 25 years, we have seen SARS, Ebola, Zika and other viruses spread undetected for months, leading to international emergencies and often devastating consequences. Even in the best US hospitals, most infectious diseases are not properly diagnosed or tracked.

But advances in two fields, genomics and information science, can transform our fight against viral threats. Ultrasensitive genome sequencing technologies are enabling the detection and characterization of viruses circulating under the radar. The advent of novel CRISPR, synthetic biology and microfluidic tools have allowed the development of rapid, ultrasensitive point-of-care diagnostics that can be deployed anywhere in the world. The resulting diagnostic and surveillance data can be integrated across healthcare nodes, from rural clinics to city hospitals, thanks to powerful new information systems. Together with advances from AI and other fields, these information systems can aid the rapid detection of infectious threats, to track their spread, and guide public health decision-making.

Over the next 25 years, the development and integration of these tools into an early-warning system embedded into healthcare systems around the world could revolutionize infectious disease detection and response. But this will only happen with a commitment from the global community.

Els Torreele

Executive director, Médecins Sans Frontières Access Campaign.

Of the many biomedical advances made by the scientific community, only those that can generate large financial profits are taken up for development by for-profit companies. This leaves many gaps—but also opportunities—in regard to developing new treatments to meet public health needs.

My hope is that the scientific community will step up and target efforts to develop innovative therapeutics and other health tools for populations across the world. This includes people affected by tuberculosis, hepatitis, Ebola, advanced HIV, neglected tropical diseases, vaccine-preventable diseases, antimicrobial resistance, snakebite—the list goes on. The creativity and brainpower of the global research community are required to find solutions addressing these grave human needs.

But to do this, we need a paradigm shift such that medicines are no longer lucrative market commodities but are global public health goods—available to all those who need them. This will require members of the scientific community to go beyond their role as researchers and actively engage in R&D policy reform mandating health research in the public interest and ensuring that the results of their work benefit many more people. The global research community can lead the way toward public-interest-driven health innovation, by undertaking collaborative open science and piloting not-for-profit R&D strategies that positively impact people’s lives globally.

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27 january 2020.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Looking forward 25 years: the future of medicine. Nat Med 25 , 1804–1807 (2019). https://doi.org/10.1038/s41591-019-0693-y

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Generative AI develops potential new drugs for antibiotic-resistant bacteria

Stanford Medicine researchers devise a new artificial intelligence model, SyntheMol, which creates recipes for chemists to synthesize the drugs in the lab.

March 28, 2024 - By Rachel Tompa

Acinetobacter baumannii infection is a leading cause of death related to antibiotic resistance. Stanford Medicine researchers employed artificial intelligence to provide recipes for drugs that can treat it.  Kateryna Kon /Shutterstock.com

With nearly 5 million deaths linked to antibiotic resistance globally every year, new ways to combat resistant bacterial strains are urgently needed.

Researchers at Stanford Medicine and McMaster University are tackling this problem with generative artificial intelligence. A new model, dubbed SyntheMol (for synthesizing molecules), created structures and chemical recipes for six novel drugs aimed at killing resistant strains of Acinetobacter baumannii, one of the leading pathogens responsible for antibacterial resistance-related deaths.

The researchers described their model and experimental validation of these new compounds in a study published March 22 in the journal Nature Machine Intelligence .

“There’s a huge public health need to develop new antibiotics quickly,” said James Zou , PhD, an associate professor of biomedical data science and co-senior author on the study. “Our hypothesis was that there are a lot of potential molecules out there that could be effective drugs, but we haven’t made or tested them yet. That’s why we wanted to use AI to design entirely new molecules that have never been seen in nature.”

Before the advent of generative AI, the same type of artificial intelligence technology that underlies large language models like ChatGPT, researchers had taken different computational approaches to antibiotic development. They used algorithms to scroll through existing drug libraries, identifying those compounds most likely to act against a given pathogen. This technique, which sifted through 100 million known compounds , yielded results but just scratched the surface in finding all the chemical compounds that could have antibacterial properties.

Kyle Swanson

“Chemical space is gigantic,” said Kyle Swanson , a Stanford computational science doctoral student and co-lead author on the study. “People have estimated that there are close to 10 60 possible drug-like molecules. So, 100 million is nowhere close to covering that entire space.”

Hallucinating for drug development

Generative AI’s tendency to “hallucinate,” or make up responses out of whole cloth, could be a boon when it comes to drug discovery, but previous attempts to generate new drugs with this kind of AI resulted in compounds that would be impossible to make in the real world, Swanson said. The researchers needed to put guardrails around SyntheMol’s activity — namely, to ensure that any molecules the model dreamed up could be synthesized in a lab.

“We’ve approached this problem by trying to bridge that gap between computational work and wet lab validation,” Swanson said.

The model was trained to construct potential drugs using a library of more than 130,000 molecular building blocks and a set of validated chemical reactions. It generated not only the final compound but also the steps it took with those building blocks, giving the researchers a set of recipes to produce the drugs.

The researchers also trained the model on existing data of different chemicals’ antibacterial activity against A. baumannii . With these guidelines and its building block starting set, SyntheMol generated around 25,000 possible antibiotics and the recipes to make them in less than nine hours. To prevent the bacteria from quickly developing resistance to the new compounds, researchers then filtered the generated compounds to only those that were dissimilar from existing compounds.

“Now we have not just entirely new molecules but also explicit instructions for how to make those molecules,” Zou said.

A new chemical space

The researchers chose the 70 compounds with the highest potential to kill the bacterium and worked with the Ukrainian chemical company Enamine to synthesize them. The company was able to efficiently generate 58 of these compounds, six of which killed a resistant strain of A. baumannii when researchers tested them in the lab. These new compounds also showed antibacterial activity against other kinds of infectious bacteria prone to antibiotic resistance, including E. coli, Klebsiella pneumoniae and MRSA.

The scientists were able to further test two of the six compounds for toxicity in mice, as the other four didn’t dissolve in water. The two they tested seemed safe; the next step is to test the drugs in mice infected with A. baumannii to see if they work in a living body, Zou said.

The six compounds are vastly different from each other and from existing antibiotics. The researchers don’t know how their antibacterial properties work at the molecular level, but exploring those details could yield general principles relevant to other antibiotic development.

“This AI is really designing and teaching us about this entirely new part of the chemical space that humans just haven’t explored before,” Zou said.

Zou and Swanson are also refining SyntheMol and broadening its reach. They’re collaborating with other research groups to use the model for drug discovery for heart disease and to create new fluorescent molecules for laboratory research.

The study was funded by the Weston Family Foundation, the David Braley Centre for Antibiotic Discovery, the Canadian Institutes of Health Research, M. and M. Heersink, the Chan-Zuckerberg Biohub, and the Knight-Hennessy scholarship.

For more news about responsible AI in health and medicine,  sign up  for the RAISE Health newsletter.

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• Rachel Tompa Rachel Tompa is a freelance science writer.

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu .

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October 12, 2023

"A new era in brain science”: Salk researchers unveil human brain cell atlas

The new research, part of the NIH BRAIN Initiative, paves the way toward treating, preventing, and curing brain disorders

Home - Salk News - “A new era in brain science”: Salk researchers unveil human brain cell atlas

“A new era in brain science”: Salk researchers unveil human brain cell atlas

LA JOLLA—Salk Institute researchers, as part of a larger collaboration with research teams around the world, analyzed more than half a million brain cells from three human brains to assemble an atlas of hundreds of cell types that make up a human brain in unprecedented detail.

The research, published in a special issue of the journal Science on October 13, 2023, is the first time that techniques to identify brain cell subtypes originally developed and applied in mice have been applied to human brains.

“These papers represent the first tests of whether these approaches can work in human brain samples, and we were excited at just how well they translated,” says Professor  Joseph Ecker , director of Salk’s Genomic Analysis Laboratory and a Howard Hughes Medical Institute investigator. “This is really the beginning of a new era in brain science, where we will be able to better understand how brains develop, age, and are affected by disease.”

The new work is part of the National Institute of Health’s Brain Research Through Advancing Innovative Neurotechnologies Initiative , or The BRAIN Initiative , an effort launched in 2014 to describe the full plethora of cells—as characterized by many different techniques—in mammalian brains. Salk is one of three institutions awarded grants to act as central players in generating data for the NIH BRAIN Initiative Cell Census Network, BICCN .

Every cell in a human brain contains the same sequence of DNA, but in different cell types different genes are copied onto strands of RNA for use as protein blueprints. This ultimate variation in which proteins are found in which cells—and at what levels—allows the vast diversity in types of brain cells and the complexity of the brain. Knowing which cells rely on which DNA sequences to function is critical not only to understanding how the brain works, but also how mutations in DNA can cause brain disorders and, relatedly, how to treat those disorders.

“Once we scale up our techniques to a large number of brains, we can start to tackle questions that we haven’t been able to in the past,” says Margarita Behrens , a research professor in Salk’s Computational Neurobiology Laboratory and a co-principal investigator of the new work.

In 2021, Ecker and Behrens led the Salk team that profiled 161 types of cells in the mouse brain , based on methyl chemical markers along DNA that specify when genes are turned on or off. This kind of DNA regulation, called methylation, is one level of cellular identity.

In the new paper, the researchers used the same tools to determine the methylation patterns of DNA in more than 500,000 brain cells from 46 regions in the brains of three healthy adult male organ donors. While mouse brains are largely the same from animal to animal, and contain about 80 million neurons, human brains vary much more and contain about 80 billion neurons.

“It’s a big jump from mice to humans and also introduces some technical challenges that we had to overcome,” says Behrens. “But we were able to adapt things that we had figured out in mice and still get very high quality results with human brains.”

At the same time, the researchers also used a second technique, which analyzed the three-dimensional structure of DNA molecules in each cell to get additional information about what DNA sequences are being actively used. Areas of DNA that are exposed are more likely to be accessed by cells than stretches of DNA that are tightly folded up.

"This is the first time we’ve looked at these dynamic genome structures at a whole new level of cell type granularity in the brain, and how those structures may regulate which genes are active in which cell types,” says Jingtian Zhou, co-first author of the new paper and a postdoctoral researcher in Ecker’s lab.

Other research teams whose work is also published in the special issue of Science used cells from the same three human brains to test their own cell profiling techniques, including a group at UC San Diego led by Bing Ren—also a co-author in Ecker and Behrens’ study. Ren’s team revealed a link between specific brain cell types and neuropsychiatric disorders, including schizophrenia, bipolar disorder, Alzheimer’s disease, and major depression. Additionally, the team developed artificial intelligence deep learning models that predict risk for these disorders.

Other groups in the global collaboration focused on measuring levels of RNA to group cells together into subtypes. The groups found a high level of correspondence in each brain region between which genes were activated, based on the DNA studies by Ecker and Behrens’ team, and which genes were found to be transcribed into RNA.

Since the new Salk research was intended as a pilot study to test the efficacy of the techniques in human brains, the researchers say they can’t yet draw conclusions about how many cell types they might uncover in the human brain or how those types differ between mice and humans.

“The potential to find unique cell types in humans that we don’t see in mice is really exciting,” says Wei Tian, co-first author of the new paper and a staff scientist in Ecker’s lab. “We’ve made amazing progress but there are always more questions to ask.”

In 2022, the NIH Brain Initiative launched a new BRAIN Initiative Cell Atlas Network (BICAN), which will follow up the BICCN efforts. At Salk, a new Center for Multiomic Human Brain Cell Atlas funded through BICAN aims to study cells from over a dozen human brains and ask questions about how the brain changes during development, over people’s lifespans, and with disease. That more detailed work on a larger number of brains, Ecker says, will pave the way toward a better understanding of how certain brain cell types go awry in brain disorders and diseases.

“We want to have a full understanding of the brain across the lifespan so that we can pinpoint exactly when, how, and in which cell types things go wrong with disease—and potentially prevent or reverse those harmful changes,” says Ecker.

View the full BRAIN Initiative paper package here , including research from collaborators around the globe.

Other authors of the paper are Anna Bartlett, Qiurui Zeng, Hanqing Liu, Rosa G. Castanon, Mia Kenworthy, Jordan Altshul, Cynthia Valadon, Andrew Aldridge, Joseph R. Nery, Huaming Chen, Jiaying Xu, Nicholas D. Johnson, Jacinta Lucero, Julia K. Osteen, Nora Emerson, Jon Rink, Jasper Lee, Michelle Liem, Naomi Claffey and Caz O'Connor of Salk; Yang Li and Bing Ren of the Ludwig Institute for Cancer Research at UC San Diego; Kimberly Siletti and Sten Linnarsson of the Karolinska Institutet; Anna Marie Yanny, Julie Nyhus, Nick Dee, Tamara Casper, Nadiya Shapovalova, Daniel Hirschstein, Rebecca Hodge, Boaz P. Levi and Ed Lein of the Allen Institute for Brain Science; and C. Dirk Keene of the University of Washington.

The work was supported by grants from the National Institute of Mental Health (U01MH121282, UM1 MH130994, NIMH U01MH114812), the National Institutes of Health BRAIN Initiative (NCI CCSG: P30 014195),  the Nancy and Buster Alvord Endowment, and the Howard Hughes Medical Institute.

DOI: 10.1126/science.adf5357

PUBLICATION INFORMATION

Single-cell DNA methylation and 3D genome architecture in the human brain

Wei Tian, Jingtian Zhou, Anna Bartlett, Qiurui Zeng, Hanqing Liu, Rosa G. Castanon, Mia Kenworthy, Jordan Altshul, Cynthia Valadon, Andrew Aldridge, Joseph R. Nery, Huaming Chen, Jiaying Xu, Nicholas D. Johnson, Jacinta Lucero, Julia K. Osteen, Nora Emerson, Jon Rink, Jasper Lee, Yang Li, Kimberly Siletti, Michelle Liem, Naomi Claffey, Caz O’Connor, Anna Marie Yanny, Julie Nyhus, Nick Dee, Tamara Casper, Nadiya Shapovalova, Daniel Hirschstein, Rebecca Hodge, Boaz P. Levi, C. Dirk Keene, Sten Linnarsson, Ed Lein, Bing Ren, M. Margarita Behrens, Joseph R. Ecker

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New Aspects of Diabetes Research and Therapeutic Development

Both type 1 and type 2 diabetes mellitus are advancing at exponential rates, placing significant burdens on health care networks worldwide. Although traditional pharmacologic therapies such as insulin and oral antidiabetic stalwarts like metformin and the sulfonylureas continue to be used, newer drugs are now on the market targeting novel blood glucose–lowering pathways. Furthermore, exciting new developments in the understanding of beta cell and islet biology are driving the potential for treatments targeting incretin action, islet transplantation with new methods for immunologic protection, and the generation of functional beta cells from stem cells. Here we discuss the mechanistic details underlying past, present, and future diabetes therapies and evaluate their potential to treat and possibly reverse type 1 and 2 diabetes in humans.

Significance Statement

Diabetes mellitus has reached epidemic proportions in the developed and developing world alike. As the last several years have seen many new developments in the field, a new and up to date review of these advances and their careful evaluation will help both clinical and research diabetologists to better understand where the field is currently heading.

I. Introduction

Diabetes mellitus, a metabolic disease defined by elevated fasting blood glucose levels due to insufficient insulin production, has reached epidemic proportions worldwide (World Health Organization, 2020 ). Type 1 and type 2 diabetes (T1D and T2D, respectively) make up the majority of diabetes cases with T1D characterized by autoimmune destruction of the insulin-producing pancreatic beta cells. The much more prevalent T2D arises in conjunction with peripheral tissue insulin resistance and beta cell failure and is estimated to increase to 21%–33% of the US population by the year 2050 (Boyle et al., 2010 ). To combat this growing health threat and its cardiac, renal, and neurologic comorbidities, new and more effective diabetes drugs and treatments are essential. As the last several years have seen many new developments in the field of diabetes pharmacology and therapy, we determined that a new and up to date review of these advances was in order. Our aim is to provide a careful evaluation of both old and new therapies ( Fig. 1 ) in a manner that we hope will be of interest to both clinical and bench diabetologists. Instead of the usual encyclopedic approach to this topic, we provide here a targeted and selective consideration of the underlying issues, promising new treatments, and a re-examination of more traditional approaches. Thus, we do not discuss less frequently used diabetes agents, such as alpha-glucosidase inhibitors; these were discussed in other recent reviews (Hedrington and Davis, 2019 ; Lebovitz, 2019 ).

Pharmacologic targeting of numerous organ systems for the treatment of diabetes. Treatment of diabetes involves targeting of various organ systems, including the kidney by SGLT2 inhibitors; the liver, gut, and adipose tissue by metformin; and direct actions upon the pancreatic beta cell. Beta cell compounds aim to increase secretion or mass and/or to protect from autoimmunity destruction. Ultimately, insulin therapy remains the final line of diabetes treatment with new technologies under development to more tightly regulate blood glucose levels similar to healthy beta cells. hESC, human embryonic stem cell.

II. Diabetes Therapies

A. metformin.

Metformin is a biguanide originally based on the natural product galegine, which was extracted from the French lilac (Bailey, 1992 ; Rojas and Gomes, 2013 ; Witters, 2001 ). A closely related biguanide, phenformin, was also used initially for its hypoglycemic actions. Based on its successful track record as a safe, effective, and inexpensive oral medication, metformin has become the most widely prescribed oral agent in the world in treating T2D (Rojas and Gomes, 2013 ; He and Wondisford, 2015 ; Witters, 2001 ), whereas phenformin has been largely bypassed due to its unacceptably high association with lactic acidosis (Misbin, 2004 ). Unlike sulfonylureas, metformin lowers blood glucose without provoking hypoglycemia and improves insulin sensitivity (Bailey, 1992 ). Despite these well known beneficial metabolic actions, metformin’s mechanism of action and even its main target organ remain controversial. In fact, metformin has multiple mechanisms of action at the organ as well as the cellular level, which has hindered our understanding of its most important molecular effects on glucose metabolism (Witters, 2001 ). Adding to this, a specific receptor for metformin has never been identified. Metformin has actions on several tissues, although the primary foci of most studies have been the liver, skeletal muscle, and the intestine (Foretz et al., 2014 ; Rena et al., 2017 ). Metformin and phenformin clearly suppress hepatic glucose production and gluconeogenesis, and they improve insulin sensitivity in the liver and elsewhere (Bailey, 1992 ). The hepatic actions of metformin have been the most exhaustively studied to date, and there is little doubt that these actions are of some importance. However, several of the studies remain highly controversial, and there are still open questions.

One of the first reported specific molecular targets of metformin was mitochondrial complex I of the electron transport chain. Inhibition of this complex results in reduced oxidative phosphorylation and consequently decreased hepatic ATP production (El-Mir et al., 2008 ; Evans et al., 2005 ; Owen et al., 2000 ). As is the case in many other studies of metformin, however, high concentrations of the drug were found to be necessary to depress metabolism at this site (El-Mir et al., 2000 ; He and Wondisford, 2015 ; Owen et al., 2000 ). Also controversial is whether metformin works by activating 5′ AMP-activated protein kinase (AMPK), a molecular energy sensor that is known to be a major metabolic sensor in cells, or if not AMPK directly, then one of its upstream regulators such as liver kinase B2 (Zhou et al., 2001 ). Although metformin was shown to activate AMPK in several excellent studies, other studies directly contradicted the AMPK hypothesis. Most dramatic were studies showing that metformin’s actions to suppress hepatic gluconeogenesis persisted despite genetic deletion of the AMPK’s catalytic domain (Foretz et al., 2010 ). More recent studies identified additional or alternative targets, such as cAMP signaling in the liver (Miller et al., 2013 ) or glycogen synthase kinase-3 (Link, 2003 ). Other work showed that the phosphorylation of acetyl-CoA carboxylase and acetyl-CoA carboxylase 2 are involved in regulating lipid homeostasis and improving insulin sensitivity after exposure to metformin (Fullerton et al., 2013 ).

Although there are strong data to support each of these pathways, it is not entirely clear which signaling pathway(s) is most essential to the actions of metformin in hepatocytes. Metformin clearly inhibits complex I and concomitantly decreases ATP and increases AMP. The latter results in AMPK activation, reduced fatty acid synthesis, and improved insulin receptor activation, and increased AMP has been shown to inhibit adenylate cyclase to reduce cAMP and thus protein kinase A activation. Downstream, this reduces the expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase via decreased cAMP response element-binding protein, the cAMP-sensitive transcription factor. Decreased PKA also promotes ATP-dependent 6-phosphofructokinase, liver type activity via fructose 2,6-bisphosphate and reduces gluconeogenesis, as fructose-bisphosphatase 1 is inhibited by fructose 2,6-bisphosphate, along with other mechanisms (Rena et al., 2017 ; Pernicova and Korbonits, 2014 ).

More recent work has shown that metformin at pharmacological rather than suprapharmacological doses increases mitochondrial respiration and complex 1 activity and also increases mitochondrial fission, now thought to be critical for maintaining proper mitochondrial density in hepatocytes and other cells. This improvement in respiratory activity occurs via AMPK activation (Wang et al., 2019 ).

Although the liver has historically been the major suspected site of metformin action, recent studies have suggested that the gut instead of the liver is a major target, a concept supported by the increased efficacy of extended-release formulations of metformin that reside for a longer duration in the gut after their administration (Buse et al., 2016 ). An older, but in our view an important observation, is that the intravenous administration of metformin has little or no effect on blood glucose, whereas, in contrast, orally administered metformin is much more effective (Bonora et al., 1984 ). Recent imaging studies using labeled glucose have shown directly that metformin stimulates glucose uptake by the gut in patients with T2D to reduce plasma glucose concentrations (Koffert et al., 2017 ; Massollo et al., 2013 ). Additionally, it is possible that metformin may exert its effect in the gut by inducing intestinal glucagon-like peptide-1 (GLP-1) release (Mulherin et al., 2011 ; Preiss et al., 2017) to potentiate beta cell insulin secretion and by stimulating the central nervous system (CNS) to exert control over both blood glucose and liver function. Indeed, CNS effects produced by metformin have been proposed to occur via the local release of GLP-1 to activate intestinal nerve endings of ascending nerve pathways that are involved in CNS glucose regulation (Duca et al., 2015 ). Lastly, several papers have now implicated that metformin may act by altering the gut microbiome, suggesting that changes in gut flora may be critical for metformin’s actions (McCreight et al., 2016 ; Wu et al., 2017 ; Devaraj et al., 2016 ). A new study proposed that activation of the intestinal farnesoid X receptor may be the means by which microbiota alter hyperglycemia (Sun et al., 2018 ). However, these studies will require more mechanistic detail and confirmation before they can be fully accepted by the field. In addition to the action of metformin on gut flora, the production of imidazole propionate by gut microbes in turn has been shown to interfere with metformin action through a p38-dependent mechanism and AMPK inhibition. Levels of imidazole propionate are especially higher in patients with T2D who are treated with metformin (Koh et al., 2020 ).

In summary, the combined contribution of these various effects of metformin on multiple cellular targets residing in many tissues may be key to the benefits of metformin treatment on lowering blood glucose in patients with type 2 diabetes (Foretz et al., 2019 ). In contrast, exciting new work showing metformin leads to weight loss by increasing circulating levels of the peptide hormone growth differentiation factor 15 and activation of brainstem glial cell-derived neurotropic factor family receptor alpha like receptors to reduce food intake and energy expenditure works independently of metformin’s glucose-lowering effect (Coll et al., 2020 ).

B. Sulfonylureas and Beta Cell Burnout

The class of compounds known as sulfonylureas includes one of the oldest oral antidiabetic drugs in the pharmacopoeia: tolbutamide. Tolbutamide is a “first generation” oral sulfonylurea secretagogue whose clinical usefulness is due to its prompt stimulation of insulin release from pancreatic beta cells. “Second generation” sulfonylureas include drugs such as glyburide, gliclazide, and glipizide. Sulfonylureas act by binding to a high affinity sulfonylurea binding site, the sulfonylurea receptor 1 subunit of the K(ATP) channel, which closes the channel. These drugs mimic the physiologic effects of glucose, which closes the K(ATP) channel by raising cytosolic ATP/ADP. This in turn provokes beta cell depolarization, resulting in increased Ca 2+ influx into the beta cell (Ozanne et al., 1995 ; Ashcroft and Rorsman, 1989 ; Nichols, 2006 ). Importantly, sulfonylureas, and all drugs that directly increase insulin secretion, are associated with hypoglycemia, which can be severe, and which limits their widespread use in the clinic (Yu et al., 2018 ). Meglitinides are another class of oral insulin secretagogues that, like the sulfonylureas, bind to sulfonylurea receptor 1 and inhibit K(ATP) channel activity (although at a different site of action). The rapid kinetics of the meglitinides enable them to effectively blunt the postprandial glycemic excursions that are a hallmark (along with elevated fasting glucose) of T2D (Rosenstock et al., 2004). However, the need for their frequent dosing (e.g., administration before each meal) has limited their appeal to patients.

The efficacy of sulfonylureas is known to decrease over time, leading to failure of the class for effective long-term treatment of T2D (Harrower, 1991 ). More broadly, it is now widely accepted that the number of functional beta cells in humans declines during the progression of T2D. Thus, one would expect that due to this decline, all manner of oral agents intended to target the beta cell and increase its cell function (and especially insulin secretion) will fail over time (RISE Consortium, 2019 ), a process referred to as “beta cell failure” (Prentki and Nolan, 2006 ). Currently, treatments that can expand beta cell mass or improve beta cell function or survival over time are not yet available for use in the clinic. As a result, treatments that may be able to help patients cope with beta cell burnout such as islet cell transplantation, insulin pumps, or stem cell therapy are alternatives that will be discussed below.

C. Ca 2+ Channel Blockers and Type 1 Diabetes

Strategies to treat and prevent T1D have historically focused on ameliorating the toxic consequences of immune dysregulation resulting in autoimmune destruction of pancreatic beta cells. More recently, a concerted focus on alleviating the intrinsic beta cell defects (Sims et al., 2020 ; Soleimanpour and Stoffers, 2013 ) that also contribute to T1D pathogenesis have been gaining traction at both the bench and the bedside. Several recent preclinical studies suggest that Ca 2+ -induced metabolic overload induces beta cell failure (Osipovich et al., 2020 ; Stancill et al., 2017 ; Xu et al., 2012 ), with the potential that excitotoxicity contributes to beta cell demise in both T1D and T2D, similar to the well known connection between excitotoxicity and, concomitantly, increased Ca 2+ loading of the cells and neuronal dysfunction. Indeed, the use of the phenylalkylamine Ca 2+ channel blocker verapamil has been successful in ameliorating beta cell dysfunction in preclinical models of both T1D and T2D (Stancill et al., 2017 ; Xu et al., 2012 ). Verapamil is a well known blocker of L-type Ca 2+ channels, and, in normally activated beta cells, it limits Ca 2+ entry into the beta cell (Ohnishi and Endo, 1981 ; Vasseur et al., 1987 ). This would be expected to, in turn, alter the expression of many Ca 2+ influx–dependent beta cell genes (Stancill et al., 2017 ), and the evidence to date suggests it is likely that verapamil preserves beta cell function in diabetes models by repressing thioredoxin-interacting protein (TXNIP) expression and thus protecting the beta cell. This is somewhat surprising given the physiologic role of Ca 2+ is to acutely trigger insulin secretion; this process would be expected to be inhibited by L-type Ca 2+ channel blockers (Ashcroft and Rorsman, 1989 ; Satin et al., 1995 ).

Hyperglycemia is a well known inducer of TXNIP expression, and a lack of TXNIP has been shown to protect against beta cell apoptosis after inflammatory stress (Chen et al., 2008a ; Shalev et al., 2002 ; Chen et al., 2008b ). Excitingly, the use of verapamil in patients with recent-onset T1D improved beta cell function and improved glycemic control for up to 12 months after the initiation of therapy, suggesting there is indeed promise for targeting calcium and TXNIP activation in T1D. Use of verapamil for a repurposed indication in the preservation of beta cell function in T1D is attractive due its well known safety profile as well as its cardiac benefits (Chen et al., 2009 ). Although the long-term efficacy of verapamil to maintain beta cell function in vivo is unclear, a recently described TXNIP inhibitor may also show promise in suppressing the hyperglucagonemia that also contributes to glucose intolerance in T2D (Thielen et al., 2020 ). As there is a clear need for increased Ca 2+ influx into the beta cell to trigger and maintain glucose-dependent insulin secretion (Ashcroft and Rorsman, 1990 ; Satin et al., 1995 ), it remains to be seen how well regulated insulin secretion is preserved in the presence of L-type Ca 2+ channel blockers like verapamil in the system. One might speculate that reducing but not fully eliminating beta cell Ca 2+ influx might reduce TXNIP levels while preserving enough influx to maintain glucose-stimulated insulin release. Alternatively, these two phenomena may operate on entirely different time scales. At present, these issues clearly will require further investigation.

D. GLP-1 and the Incretins

Studies dating back to the 1960s revealed that administering glucose in equal amounts via the peripheral circulation versus the gastrointestinal tract led to dramatically different amounts of glucose-induced insulin secretion (Elrick et al., 1964 ; McIntyre et al., 1964 ; Perley and Kipnis, 1967 ). Gastrointestinal glucose administration greatly increased insulin secretion versus intravenous glucose, and this came to be known as the “incretin effect” (Nauck et al., 1986a ; Nauck et al., 1986b ). Subsequent work showed that release of the gut hormone GLP-1 mediated this effect such that food ingestion induced intestinal cell hormone secretion. GLP-1 so released would then circulate to the pancreas via the blood to prime beta cells to secrete more insulin when glucose became elevated because these hormones stimulated beta cell cAMP formation (Drucker et al., 1987 ). The discovery that a natural peptide corresponding to GLP-1 could be found in the saliva of the Gila monster, a desert lizard, hastened progress in the field, and ample in vitro studies subsequently confirmed that GLP-1 potentiated insulin secretion in a glucose-dependent manner. GLP-1 has little or no significant action on insulin secretion in the absence of elevated glucose (such as might typically correspond to the postprandial case or during fasting), thus minimizing the likelihood of hypoglycemia provoked by GLP-1 in treated patients (Kreymann et al., 1987 ). Although not completely understood, the glucose dependence of GLP-1 likely reflects the requirement for adenine nucleotides to close glucose-inhibited K(ATP) channels and thus subsequently activate Ca 2+ influx–dependent insulin exocytosis. Besides potentiating GSIS at the level of the beta cell, glucagon-like peptide-1 receptor (GLP-1R) agonists also decrease glucagon secretion from pancreatic islet alpha cells, reduce gastric emptying, and may also increase beta cell proliferation, among other cellular actions (reviewed in Drucker, 2018 ; Muller et al., 2019).

Intense interest in the incretins by basic scientists, clinicians, and the pharma community led to the rapid development of new drugs for treating primarily T2D. These drugs include a range of GLP-1R agonists and inhibitors of the incretin hormone degrading enzyme dipeptidyl peptidase 4 (DPP4), whose targeting increases the half-lives of GLP-1 and gastric inhibitory polypeptide (GIP) and thereby increases protein hormone levels in plasma. GLP-1R agonists have been associated with not only a lowering of plasma glucose but also weight loss, decreased appetite, reduced risk of cardiovascular events, and other favorable outcomes (Gerstein et al., 2019; Hernandez et al., 2018; Husain et al., 2019; Marso et al., 2016a; Marso et al., 2016b ; Buse et al., 2004). Regarding their untoward actions, although hypoglycemia is not a major concern, there have been reports of pancreatitis and pancreatic cancer from use of GLP-1R agonists. However, a recent meta-analysis covering four large-scale clinical trials and over 33,000 participants noted no significantly increased risk for pancreatitis/pancreatic cancer in patients using GLP-1R agonists (Bethel et al., 2018).

Ongoing and future developments in the use of proglucagon-derived peptides such as GLP-1 and glucagon include the use of combined GLP-1/GIP, glucagon/GLP-1, and agents targeting all three peptides in combination (reviewed in Alexiadou and Tan, 2020 ). Although short-term infusions of GLP-1 with GIP failed to yield metabolic benefits beyond those seen with GLP-1 alone (Bergmann et al., 2019 ), several GLP-1/GIP dual agonists are currently in development and have shown promising metabolic results in clinical trials (Frias et al., 2017 ; Frias et al., 2020 ; Frias et al., 2018 ). At the level of the pancreatic islet, beneficial effects of dual GLP-1/GIP agonists may be related to imbalanced and biased preferences of these agonists for the gastric inhibitory polypeptide receptor over the GLP-1R (Willard et al., 2020 ) and possibly were not simply to dual hormone agonism in parallel. Dual glucagon/GLP-1 agonist therapy has also been shown to have promising metabolic effects in humans (Ambery et al., 2018 ; Tillner et al., 2019 ). Oxyntomodulin is a natural dual glucagon/GLP-1 receptor agonist and proglucagon cleavage product that is also secreted from intestinal enteroendocrine cells, which has beneficial effects on insulin secretion, appetite regulation, and body weight in both humans and rodents (Cohen et al., 2003 ; Dakin et al., 2001 ; Dakin et al., 2002 ; Shankar et al., 2018 ; Wynne et al., 2005 ). Interestingly, alpha cell crosstalk to beta cells through the combined effects of glucagon and GLP-1 is necessary to obtain optimal glycemic control, suggesting a potential pathway for therapeutic dual glucagon/GLP-1 agonism within the islets of patients with T2D (Capozzi et al., 2019a ; Capozzi et al., 2019b ). Although the early results appear promising, more studies will be necessary to better understand the mechanistic and clinical impacts of these multiagonist agents.

E. DPP4 Inhibitors

Inhibition of DPP4, the incretin hormone degrading enzyme, is one of the most common T2D treatments to increase GLP-1 and GIP plasma hormone levels. These DPP4 inhibitors or “gliptins” are generally used in conjunction with other T2D drugs such as metformin or sulfonylureas to obtain the positive benefits discussed above (Lambeir et al., 2008 ). DPP4 is a primarily membrane-bound peptidase belonging to the serine peptidase/prolyl oligopeptidase gene family, which cleaves a large number of substrates in addition to the incretin hormones (Makrilakis, 2019 ). DPP4 inhibitors provide glucose-lowering benefits while being generally well tolerated, and the variety of available drugs (including sitagliptin, saxagliptin, vildagliptin, alogliptin, and linagliptin) with slightly different dosing frequency, half-life, and mode of excretion/metabolism allows for use in multiple patient populations (Makrilakis, 2019 ). This includes the elderly and individuals with renal or hepatic insufficiency (Makrilakis, 2019 ).

Although hypoglycemia is not a concern for DPP4 inhibitor use, other considerations should be made. DPP4 inhibitors tend to be more expensive than metformin or other second-line oral drugs in addition to having more modest glycemic effects than GLP-1R agonists (Munir and Lamos, 2017 ). Finally, meta-analysis of randomized and observational studies concluded that heart failure in patients with T2D was not associated with use of DPP4 inhibitors; however, this study was limited by the short follow-up and lack of high-quality data (Li et al., 2016 ). Thus, the US Food and Drug Administration (FDA) did recommend assessing risk of heart failure hospitalization in patients with pre-existing cardiovascular disease, prior heart failure, and chronic kidney disease when using saxagliptin and alogliptin (Munir and Lamos, 2017 ).

F. Sodium Glucose Cotransporter 2 Inhibitors

A recent development in the field of T2D drugs are sodium glucose cotransporter 2 (SGLT2) inhibitors, which have an interesting and very different mechanism of action. Within the proximal tubule of the nephron, SGLT2 transports ingested glucose into the lumen of the proximal tubule between the epithelial layers, thereby reclaiming glucose by this reabsorption process (reviewed in Vallon, 2015 ). SGLT2 inhibitors target this transporter and increase glucose in the tubular fluid and ultimately increase it in the urine. In patients with diabetes, SGLT2 inhibition results in a lowering of plasma glucose with urine glucose content rising substantially (Adachi et al., 2000 ; Vallon, 2015 ). These drugs, although they are relatively new, have become an area of great interest for not only patients with T2D (Grempler et al., 2012 ; Imamura et al., 2012 ; Meng et al., 2008 ; Nomura et al., 2010 ) but also for patients with T1D (Luippold et al., 2012 ; Mudaliar et al., 2012 ). Part of their appeal also rests on reports that their use can lead to a statistically significant decline in cardiac events that are known to occur secondarily to diabetes, possibly independently of plasma glucose regulation (reviewed in Kurosaki and Ogasawara, 2013 ). Although the long-term consequences of their clinical use cannot yet be determined, raising the glucose content of the urogenital tract leads to an increased risk of urinary tract infections and other related infections in some patients (Kurosaki and Ogasawara, 2013 ).

Another recent concern about the use of SGLT2 inhibitors has been the development of normoglycemic diabetic ketoacidosis (DKA). Despite the efficacy of SGLT2 inhibitors, observations of hyperglucagonemia in patients with euglycemic DKA has led to a number of recent studies focused on SGLT2 actions on pancreatic islets. Initial studies of isolated human islets treated with small interfering RNA directed against SGLT2 and/or SGLT2 inhibitors demonstrated increased glucagon release. These studies were complemented by the finding of elevations in glucagon release in mice that were administered SGLT2 inhibitors in vivo (Bonner et al., 2015 ). Insights into the possible mechanistic links between SGLT2 inhibition, DKA frequency, and glucagon secretion in humans may relate to the observation of heterogeneity in SGLT2 expression, as SGLT2 expression appears to have a high frequency of interdonor and intradonor variability (Saponaro et al., 2020 ). More recently, both insulin and GLP-1 have been demonstrated to modulate SGLT2-dependent glucagon release through effects on somatostatin release from delta cells (Vergari et al., 2019 ; Saponaro et al., 2019 ), suggesting potentially complex paracrine effects that may affect the efficacy of these compounds.

On the other hand, several recent studies question that the development of euglycemic DKA after SGLT2 inhibitor therapy may be through alpha cell–dependent mechanisms. Three recent studies found no effect of SGLT2 inhibitors to promote glucagon secretion in mouse and/or rat models and could not detect SGLT2 expression in human alpha cells (Chae et al., 2020 ; Kuhre et al., 2019 ; Suga et al., 2019 ). A fourth study demonstrated only a brief transient effect of SGLT2 inhibition to raise circulating glucagon concentrations in immunodeficient mice transplanted with human islets, which returned to baseline levels after longer exposures to SGLT2 inhibitors (Dai et al., 2020 ). Furthermore, SGLT2 protein levels were again undetectable in human islets (Dai et al., 2020 ). These results could suggest alternative islet-independent mechanisms by which patients develop DKA, including alterations in ketone generation and/or clearance, which underscore the additional need for further studies both in molecular models and at the bedside. Nevertheless, SGLT2 inhibitors continue to hold promise as a valuable therapy for T2D, especially in the large segment of patients who also have superimposed cardiovascular risk (McMurray et al., 2019; Wiviott et al., 2019; Zinman et al., 2015).

G. Thiazolidinediones

Once among the most commonly used oral agents in the armamentarium to treat T2D, thiazolidinediones (TZDs) were clinically popular in their utilization to act specifically as insulin sensitizers. TZDs improve peripheral insulin sensitivity through their action as peroxisome proliferator-activated receptor (PPAR) γ agonists, but their clinical use fell sharply after studies suggested a connection between cardiovascular toxicity with rosiglitazone and bladder cancer risk with pioglitazone (Lebovitz, 2019 ). Importantly, an FDA panel eventually removed restrictions related to cardiovascular risk with rosiglitazone in 2013 (Hiatt et al., 2013 ). Similarly, concerns regarding use of bladder cancer risk with pioglitazone were later abated after a series of large clinical studies found that pioglitazone did not increase bladder cancer (Lewis et al., 2015 ; Schwartz et al., 2015 ). However, usage of TZDs had already substantially decreased and has not since recovered.

Although concerns regarding edema, congestive heart failure, and fractures persist with TZD use, there have been several studies suggesting that TZDs protect beta cell function. In the ADOPT study, use of rosiglitazone monotherapy in patients newly diagnosed with T2D led to improved glycemic control compared with metformin or sulfonylureas (Kahn et al., 2006). Later analyses revealed that TZD-treated subjects had a slower deterioration of beta cell function than metformin- or sulfonylurea-treated subjects (Kahn et al., 2011). Furthermore, pioglitazone use improved beta cell function in the prevention of T2D in the ACT NOW study (Defronzo et al., 2013; Kahn et al., 2011). Mechanistically, it is unclear if TZDs lead to beneficial beta cell function through direct effects or through indirect effects of reduced beta cell demand due to enhanced peripheral insulin sensitivity. Indeed, a beta cell–specific knockout of PPAR γ did not impair glucose homeostasis, nor did it impair the antidiabetic effects of TZD use in mice (Rosen et al., 2003 ). However, other reports demonstrated PPAR-responsive elements within the promoters of both glucose transporter 2 and glucokinase that enhance beta cell glucose sensing and function, which could explain beta cell–specific benefits for TZDs (Kim et al., 2002 ; Kim et al., 2000 ). Furthermore, TZDs have been shown to improve beta cell function by upregulating cholesterol transport (Brunham et al., 2007 ; Sturek et al., 2010 ). Additionally, use of TZDs in the nonobese diabetic (NOD) mouse model of T1D augmented the beta cell unfolded protein response and prevented beta cell death, suggesting potential benefits for TZDs in both T1D and T2D (Evans-Molina et al., 2009 ; Maganti et al., 2016 ). With a now refined knowledge of demographics in which to avoid TZD treatment due to adverse effects, together with genetic approaches to identify candidates more likely to respond effectively to TZD therapy (Hu et al., 2019 ; Soccio et al., 2015 ), it remains to be seen if TZD therapy will return to more prominent use in the treatment of diabetes.

H. Insulin and Beyond: The Use of “Smart” Insulin and Closed Loop Systems in Diabetes Treatment

Due to recombinant DNA technology, numerous insulin analogs are now available in various forms ranging from fast acting crystalline insulin to insulin glargine; all of these analogs exhibit equally effective insulin receptor binding. Most are generated by altering amino acids in the B26–B30 region of the molecule (Kurtzhals et al., 2000 ). The American Diabetes Association delineates these insulins by their 1) onset or time before insulin reaches the blood stream, 2) peak time or duration of maximum blood glucose–lowering efficacy, and 3) the duration of blood glucose–lowering time. Insulin administration is independent of the residuum of surviving and/or functioning beta cells in the patient and remains the principal pharmacological treatment of both T1D and T2D. The availability of multiple types of delivery methods, i.e., insulin pens, syringes, pumps, and inhalants, provides clinicians with a solid and varied tool kit with which to treat diabetes. The downsides, however, are that 1) hypoglycemia is a constant threat, 2) proper insulin doses are not trivial to calculate, 3) compliance can vary especially in children and young adults, and 4) there can be side effects of a variety of types. Nonetheless, insulin therapy remains a mainstay treatment of diabetes.

To eliminate the downsides of insulin therapy, research in the past several decades has worked toward generating glucose-sensitive or “smart” insulin molecules. These molecules change insulin bioavailability and become active only upon high blood glucose using glucose-binding proteins such as concanavalin A, glucose oxidase to alter pH sensitivity, and phenylboronic acid (PBA), which forms reversible ester linkages with diol-containing molecules including glucose itself (reviewed in Rege et al., 2017 ). Indeed, promising recent studies included various PBA moieties covalently bonded to an acylated insulin analog (insulin detemir, which contains myristic acid coupled to Lys B29 ). The detemir allows for binding to serum albumin to prolong insulin’s half-life in the circulation, and PBA provided reversible glucose binding (Chou et al., 2015 ). The most promising of the PBA-modified conjugates showed higher potency and responsiveness in lowering blood glucose levels compared with native insulin in diabetic mouse models and decreased hypoglycemia in healthy mice, although the molecular mechanisms have not yet been determined (Chou et al., 2015 ).

An additional active area of research includes structurally defining the interaction between insulin and the insulin receptor ectodomain. Importantly, a major conformational change was discovered that may be exploited to impair insulin receptor binding under hypoglycemic conditions (Menting et al., 2013 ; Rege et al., 2017 ). Challenges in the design, testing, and execution of glucose-responsive insulins may be overcome by the adaptation of novel modeling approaches (Yang et al., 2020 ), which may allow for more rapid screening of candidate compounds.

Technologies have also progressed in the field of artificial pancreas design and development. Currently two “closed loop” systems are now available: Minimed 670G from Medtronic and Control-IQ from Tandem Diabetes Care. Both systems use a continuous glucose monitor, insulin pump, and computer algorithm to predict correct insulin doses and administer them in real time. Such algorithm systems also take into account insulin potency, the rate of blood glucose increase, and the patient’s heart rate and temperature to adjust insulin delivery levels during exercise and after a meal. In addition, so-called “artificial pancreas” systems have also been clinically tested, which use both insulin and glucagon and as such result in fewer reports of hypoglycemic episodes (El-Khatib et al., 2017 ). These types of systems will continue to become more popular as the development of room temperature–stable glucagon analogs continue, such as GVOKE by Xeris Pharmaceuticals (currently available in an injectable syringe) and Baqsimi, a nasally administered glucagon from Eli Lilly.

I. Present and Future Therapies: Beta Cell Transplantation, Replication, and Immune Protection

1. islet transplantation.

The idea to use pancreatic allo/xenografts to treat diabetes remarkably dates back to the late 1800s (Minkowski, 1892 ; Pybus, 1924 ; Williams, 1894 ). Before proceeding to the discovery of insulin (together with Best, MacLeod, and Collip), Frederick Banting also postulated the potential for transplantation of pancreatic tissue emulsions to treat diabetes in dog models in a notebook entry in 1921 (Bliss, 1982 ). Decades later, Paul Lacy, David Scharp, and colleagues successfully isolated intact functional pancreatic islets and transplanted them into rodent models (Kemp et al., 1973 ). These studies led to the initial proof of concept studies for humans, with the first successful islet transplant in a patient with T1D occurring in 1977 (Sutherland et al., 1978 ). A rapid expansion of islet transplantation, inspired by these original studies led to key observations of successfully prolonged islet engraftment by the “Edmonton protocol” whereby corticosteroid-sparing immunosuppression was applied, and islets from at least two allogeneic donors were used to achieve insulin independence (Shapiro et al., 2000 ). More recent work has focused on improving upon the efficiency and long-term engraftment of allogeneic transplants leading to more prolonged graft function (to the 5-year mark) and successful transplantation from a single islet donor (Hering et al., 2016; Hering et al., 2005 ; Rickels et al., 2013 ). Critical to these efforts to improve the success rate was the recognition that the earlier generation of immunosuppressive agents to counter tissue rejection was toxic to islets (Delaunay et al., 1997 ; Paty et al., 2002 ; Soleimanpour et al., 2010 ) and that more appropriate and less toxic agents were needed (Hirshberg et al., 2003 ; Soleimanpour et al., 2012 ).

Certainly, islet transplantation as a therapeutic approach for patients with T1D has been scrutinized due to several challenges, including (but not limited to) the lack of available donor supply to contend with demand, limited long-term functional efficacy of islet allografts, the potential for re-emergence of autoimmune islet destruction and/or metabolic overload-induced islet failure, and significant adverse effects of prolonged immunosuppression (Harlan, 2016 ). Furthermore, although islet transplantation is not currently available for individuals with T2D, simultaneous pancreas-kidney transplantation in T2D had similar favorable outcomes to simultaneous pancreas-kidney transplantation in T1D; therefore, islet-kidney transplantation may eventually be a feasible option to treat T2D, as patients will already be on immunosuppressors (Sampaio et al., 2011 ; Westerman et al., 1983 ). An additional significant obstacle is the tremendous expense associated with islet transplantation therapy. Indeed, the maintenance, operation, and utilization of an FDA-approved and Good Manufacturing Practice–compliant islet laboratory can lead to operating costs at nearly $150,000 per islet transplant, which is not cost effective for the vast majority of patients with T1D (Naftanel and Harlan, 2004 ; Wallner et al., 2016 ). At present, the focus has been to obtain FDA approval for islet allo-transplantation as a therapy for T1D to allow for insurance compensation (Hering et al., 2016; Rickels and Robertson, 2019 ). In the interim, the islet biology, stem cell, immunology, and bioengineering communities have continued the development of cell-based therapies for T1D by other approaches to overcome the challenges identified during the islet transplantation boom of the 1990s and 2000s.

2. Pharmacologic Induction of Beta Cell Replication

Besides transplantation, progress in islet cell biology and especially in developmental biology of beta cells over several decades raised the additional possibility that beta cell mass reduction in diabetes might be countered by increasing beta cell number through mitogenic means. A key method to expand pancreatic beta cell mass is through the enhancement of beta cell replication. Although the study of pancreatic beta cell replication has been an area of intense focus in the beta cell biology field for several decades, only recently has this seemed truly feasible. Seminal studies identified that human beta cells are essentially postmitotic, with a rapid phase of growth occurring in the prenatal period that dramatically tapers off shortly thereafter (Gregg et al., 2012 ; Meier et al., 2008 ). The plasticity of rodent beta cells is considerably higher than that of human beta cells (Dai et al., 2016 ), which has led to a renewed focus on validation of pharmacologic agents to enhance rodent beta cell replication using isolated and/or engrafted human islets (Bernal-Mizrachi et al., 2014 ; Kulkarni et al., 2012 ; Stewart et al., 2015 ). Indeed, a large percentage of agents that were successful when applied to rodent systems were largely unsuccessful at inducing replication in human beta cells (Bernal-Mizrachi et al., 2014 ; Kulkarni et al., 2012 ; Stewart et al., 2015 ). However, several recent studies have begun to make significant progress on successfully pushing human beta cells to replicate.

Several groups have reported successful human beta cell proliferation, both in vitro and in vivo, in response to inhibitors of the dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). These inhibitors include harmine, INDY, GNF4877, 5-iodotubericidin, leucettine-42, TG003, AZ191, CC-401, and more specific, recently developed DYRK1A inhibitors (Ackeifi et al., 2020 ). Although DYRK1A is conclusively established as the important mediator of human beta cell proliferation, comprehensively determining other cellular targets and if additional gene inhibition amplifies the proliferative response is still in process. New evidence from Wang and Stewart shows dual specificity tyrosine phosphorylation-regulated kinase 1B to be an additional mitogenic target and also describes variability in the range of activated kinases within cells and/or levels of inhibition for the many DYRK1A inhibitors listed above (Ackeifi et al., 2020 ). Interestingly, opposite to these human studies, earlier mouse studies from the Scharfmann group demonstrated that Dyrk1a haploinsufficiency leads to decreased proliferation and loss of beta cell mass (Rachdi et al., 2014b ). In addition, overexpression of Dyrk1a in mice led to beta cell mass expansion with increased glucose tolerance (Rachdi et al., 2014a ).

Although important differences in beta cell proliferative capacity have been shown between human and rodent species, there are also significant differences in the mitogenic capacity of beta cells from juvenile, adult, and pregnant individuals. This demonstrates that proliferative stimuli appear to act within the complex islet, pancreas, and whole-body environments unique to each time point. For example, the administration of the hormones platelet-derived growth factor alpha or GLP-1 result in enhanced proliferation in juvenile human beta cells yet are ineffective in adult human beta cells (Chen et al., 2011 ; Dai et al., 2017 ). This has been shown to be due to a loss of platelet-derived growth factor alpha receptor expression as beta cells age but appears to be unrelated to GLP-1 receptor expression levels (Chen et al., 2011 ). Indeed, the GLP-1 receptor is highly expressed in adult beta cells, and GLP-1 secretion increases insulin secretion, as detailed previously; however, the induction of proliferative factors such as nuclear factor of activated T cells, cytoplasmic 1; forkhead box protein 1; and cyclin A1 is only seen in juvenile islets (Dai et al., 2017 ). Human studies using cadaveric pancreata from pregnant donors also showed increased beta cell mass, yet lactogenic hormones from the pituitary or placenta (prolactin, placental lactogen, or growth hormone) are unable to stimulate proliferation in human beta cells despite their ability to produce robust proliferation in mouse beta cells (reviewed in Baeyens et al., 2016 ). Experiments overexpressing mouse versus human signal transducer and activator of transcription 5, the final signaling factor inducing beta cell adaptation, in human beta cells allows for prolactin-mediated proliferation revealing fundamental differences in prolactin pathway competency in human (Chen et al., 2015 ). Overcoming the barrier of recapitulating human pregnancy’s effect on beta cells through isolating placental cells or blood serum during pregnancy may result in the discovery of a factor(s) that facilitates the increase in beta cell mass observed during human pregnancy.

Mechanisms that stimulate beta cell proliferation have also been discovered from studying genetic mutations that result in insulinomas, spontaneous insulin-producing beta cell adenomas. The most common hereditary mutation occurs in the multiple endocrine neoplasia type 1 (MEN1) gene. Indeed, administration of a MEN1 inhibitor in addition to a GLP-1 agonist (which cannot induce proliferation alone) is able to increase beta cell proliferation in isolated human islets through synergistic activation of KRAS proto-oncogene, GTPase downstream signals (Chamberlain et al., 2014 ). Interestingly, MEN1 mutations are uncommon in sporadic insulinomas, yet assaying genomic and epigenetic changes in a large cohort of non-MEN1 insulinomas found alterations in trithorax and polycomb chromatin modifying genes that were functionally related to MEN1 (Wang et al., 2017 ). Stewart and colleagues hypothesized that changes in histone 3 lysine 27 and histone 3 lysine 4 methylation status led to increased enhancer of zeste homolog 2 and lysine demethylase 6A, decreased cyclin-dependent kinase inhibitor 1C, and thereby increased beta cell proliferation, among other phenotypes. They also proposed that these findings help to explain why increased proliferation always occurs despite broad heterogeneity of mutations found between individual insulinomas (Wang et al., 2017 ).

Although factors that induce proliferation are continuing to be discovered, there are drawbacks that still limit their clinical application. Harmine and other DYRK1A inhibitors are not beta cell specific, nor have all their cellular targets been determined (Ackeifi et al., 2020 ). Targeting other pathways to induce human beta cell proliferation such as modulation of prostaglandin E2 receptors (i.e., inhibition of prostaglandin E receptor 3 alone or in combination with prostaglandin E receptor 4 activation) showed promising increases in proliferative rate yet suffers from the same lack of specificity (Carboneau et al., 2017 ). Induction of proliferation may also come at the expense of glucose sensing as in insulinomas, which have an increased expression of “disallowed genes” and alterations in glucose transporter and hexokinase expression (Wang et al., 2017 ). A further untoward consequence that must be avoided is the production of cancerous cells through unchecked proliferation. Finally, increasing beta cell mass through low rates of proliferation may increase the pool of functional insulin-secreting cells in T2D, but without additional measures, these beta cells will still ultimately be targeted for immune cell destruction in T1D.

3. Beta Cell Stress Relieving Therapies

Metabolic, inflammatory, and endoplasmic reticulum (ER) stress contribute to beta cell dysfunction and failure in both T1D and T2D. Although reduction of metabolic overload of beta cells by early exogenous insulin therapy or insulin sensitizers can temporarily reduce loss of beta cell mass/function early in diabetes, a focus on relieving ER and inflammatory stress is also of interest to preserve beta cell health.

ER stress is a well known contributor to beta cell demise both in T1D and T2D (Laybutt et al., 2007 ; Marchetti et al., 2007 ; Marhfour et al., 2012 ; Tersey et al., 2012 ) and a target of interest in the prevention of beta cell loss in both diseases. Preclinical studies suggest that the use of chemical chaperones, including 4-phenylbutyric acid and tauroursodeoxycholic acid (TUDCA), to alleviate ER stress improves beta cell function and insulin sensitivity in mouse models of T2D (Cnop et al., 2017 ; Ozcan et al., 2006 ). Furthermore, TUDCA has been shown to preserve beta cell mass and reduce ER stress in mouse models of T1D (Engin et al., 2013 ). Interestingly, TUDCA has shown promise at improving insulin action in obese nondiabetic human subjects, yet beta cell function and insulin secretion were not assessed (Kars et al., 2010 ). A clinical trial regarding the use of TUDCA for humans with new-onset T1D is also ongoing ( {"type":"clinical-trial","attrs":{"text":"NCT02218619","term_id":"NCT02218619"}} NCT02218619 ). However, a note of caution regarding use of ER chaperones is that they may prevent low level ER stress necessary to potentiate beta cell replication during states of increased insulin demand (Sharma et al., 2015 ), suggesting that the broad use of ER chaperone therapies should be carefully considered.

The blockade of inflammatory stress has long been an area of interest for treatments of both T1D and T2D (Donath et al., 2019 ; Eguchi and Nagai, 2017 ). Indeed, use of nonsteroidal anti-inflammatory drugs (NSAIDs), which block cyclooxygenase, have been observed to improve metabolic control in patients with diabetes since the turn of the 20th century (Williamson, 1901 ). Salicylates have been shown to improve insulin secretion and beta cell function in both obese human subjects and those with T2D (Fernandez-Real et al., 2008; Giugliano et al., 1985 ). However, another NSAID, salsalate, has not been shown to improve beta cell function while improving other metabolic outcomes (Kim et al., 2014 ; Penesova et al., 2015 ), possibly suggesting distinct mechanisms of action for anti-inflammatory compounds. The regular use of NSAIDs to enhance metabolic outcomes is also often limited to the tolerability of long-term use of these agents due to adverse effects. Recently, golilumab, a monoclonal antibody against the proinflammatory cytokine tumor necrosis factor alpha, was demonstrated to improve beta cell function in new-onset T1D, suggesting that targeting the underlying inflammatory milieu may have benefits to preserve beta cell mass and function in T1D (Quattrin et al., 2020). Taken together, both new and old approaches to target beta cell stressors still remain of long-term interest to improve beta cell viability and function in both T1D and T2D.

3. New Players to Induce Islet Immune Protection

Countless researchers have expended intense industry to determine T1D disease etiology and treatments focused on immunotherapy and tolerogenic methods. Multiple, highly comprehensive reviews are available describing these efforts (Goudy and Tisch, 2005 ; Rewers and Gottlieb, 2009 ; Stojanovic et al., 2017 ). Here we will focus on the protection of beta cells through programmed cell death protein-1 ligand (PD-L1) overexpression, major histocompatibility complex class I, A, B, C (HLA-A,B,C) mutated human embryonic stem cell–derived beta cells, and islet encapsulation methods.

Cancer immunotherapies that block immune checkpoints are beneficial for treating advanced stage cancers, yet induction of autoimmune diseases, including T1D, remains a potential side effect (Stamatouli et al., 2018 ; Perdigoto et al., 2019 ). A subset of these drugs target either the programmed cell death-1 protein on the surface of activated T lymphocytes or its receptor PD-L1 (Stamatouli et al., 2018 ; Perdigoto et al., 2019 ). PD-L1 expression was found in insulin-positive beta cells from T1D but not insulin-negative islets or nondiabetic islets, leading to the hypothesis that PD-L1 is upregulated in an attempt to drive immune cell attenuation (Osum et al., 2018 ; Colli et al., 2018 ). Adenoviral overexpression of PD-L1 specifically in beta cells rescued hyperglycemia in the NOD mouse model of T1D, but these animals eventually succumbed to diabetes by the study’s termination (El Khatib et al., 2015 ). A more promising report from Ben Nasr et al. ( 2017 ) demonstrated that pharmacologically or genetically induced overexpression of PD-L1 in hematopoietic stem and progenitor cells inhibited beta cell autoimmunity in the NOD mouse as well as in vitro using human hematopoietic stem and progenitor cells from patients with T1D.

As mentioned above, islet transplantation to treat T1D is limited by islet availability, cost, and the requirement for continuous immunosuppression. Islet cells generated by differentiating embryonic or induced pluripotent stem (iPS) cells could circumvent these limitations. Ideally, iPS-derived beta cells could be manipulated to eliminate the expression of polymorphic HLA-A,B,C molecules, which were found to be upregulated in T1D beta cells (Bottazzo et al., 1985 ; Richardson et al., 2016 ). These molecules allow peptide presentation to CD8+ T cells or cytotoxic T lymphocytes and may lead to beta cell removal. Interestingly, remaining insulin-positive cells in T1D donor pancreas are not HLA-A,B,C positive (Nejentsev et al., 2007; Rodriguez-Calvo et al., 2015 ). However, current differentiation protocols are still limited in their ability to produce fully glucose-responsive beta cells without transplantation into animal models to induce mature characteristics. Additionally, use of iPS-derived beta cells will still lead to concerns regarding DNA mutagenesis resulting from the methods used to obtain pluripotency or teratoma formation from cells that have escaped differentiation.

Encapsulation devices would protect islets or stem cells from immune cell infiltration while allowing for the proper exchange of nutrients and hormones. Macroencapsulation uses removable devices that would help assuage fears surrounding mutation or tumor formation; indeed, the first human trial using encapsulated hESC-derived beta cells will be completed in January 2021 ( {"type":"clinical-trial","attrs":{"text":"NCT02239354","term_id":"NCT02239354"}} NCT02239354 ). Macroencapsulation of islets prior to transplantation using various alginate-based hydrogels has historically been impeded by a strong in vivo foreign body immune response (Desai and Shea, 2017 ; Doloff et al., 2017 ; Pueyo et al., 1993 ). More recently, chemically modified forms of alginate that avoid macrophage recognition and fibrous deposition have been successfully used in rodents and for up to 6 months in nonhuman primates (Vegas et al., 2016 ). Indeed, Bochenek et al. ( 2018 ) successfully transplanted alginate protected islets for 4 months without immunosuppression in the bursa omentalis of nonhuman primates demonstrating the feasibility for this approach to be extended to humans. It remains to be seen if these devices will be successful for long-term use, perhaps decades, in patients with diabetes.

III. Summary

Although existing drug therapies using classic oral antidiabetic drugs like sulfonylureas and metformin or injected insulin remain mainstays of diabetes treatment, newer drugs based on incretin hormone actions or SGLT2 inhibitors have increased the pharmacological armamentarium available to diabetologists ( Fig. 1 ). However, the explosion of progress in beta cell biology has identified potential avenues that can increase beta cell mass in sophisticated ways by employing stem cell differentiation or enhancement of beta cell proliferation. Taken together, there should be optimism that the increased incidence of both T1D and T2D is being matched by the creativity and hard work of the diabetes research community.

Abbreviations

Authorship contributions.

Wrote and contributed to the writing of the manuscript: Satin, Soleimanpour, Walker

This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [Grant R01-DK46409] (to L.S.S.), [Grant R01-DK108921] (to S.A.S.), and [Grant P30-DK020572 pilot and feasibility grant] (to S.A.S.), the Juvenile Diabetes Research Foundation (JDRF) [Grant CDA-2016-189] (to L.S.S. and S.A.S.), [Grant SRA-2018-539] (to S.A.S.), and [Grant COE-2019-861] (to S.A.S.), and the US Department of Veterans Affairs [Grant I01 BX004444] (to S.A.S.). The JDRF Career Development Award to S.A.S. is partly supported by the Danish Diabetes Academy and the Novo Nordisk Foundation.

https://doi.org/10.1124/pharmrev.120.000160

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FACT SHEET: President   Biden Issues Executive Order and Announces New Actions to Advance Women’s Health Research and   Innovation

In his State of the Union address, President Biden laid out his vision for transforming women’s health research and improving women’s lives all across America. The President called on Congress to make a bold, transformative investment of $12 billion in new funding for women’s health research. This investment would be used to create a Fund for Women’s Health Research at the National Institutes of Health (NIH) to advance a cutting-edge, interdisciplinary research agenda and to establish a new nationwide network of research centers of excellence and innovation in women’s health—which would serve as a national gold standard for women’s health research across the lifespan.

It is long past time to ensure women get the answers they need when it comes to their health—from cardiovascular disease to autoimmune diseases to menopause-related conditions. To pioneer the next generation of discoveries, the President and the First Lady launched the first-ever White House Initiative on Women’s Health Research , which aims to fundamentally change how we approach and fund women’s health research in the United States.

Today, President Biden is signing a new Executive Order that will direct the most comprehensive set of executive actions ever taken to expand and improve research on women’s health. These directives will ensure women’s health is integrated and prioritized across the federal research portfolio and budget, and will galvanize new research on a wide range of topics, including women’s midlife health.

The President and First Lady are also announcing more than twenty new actions and commitments by federal agencies, including through the U.S. Department of Health and Human Services (HHS), the Department of Defense (DoD), the Department of Veterans Affairs (VA), and the National Science Foundation (NSF). This includes the launch of a new NIH-wide effort that will direct key investments of $200 million in Fiscal Year 2025 to fund new, interdisciplinary women’s health research—a first step towards the transformative central Fund on Women’s Health that the President has called on Congress to invest in. These actions also build on the First Lady’s announcement last month of the Advanced Research Projects Agency for Health (ARPA-H) Sprint for Women’s Health , which committed $100 million towards transformative research and development in women’s health.

Today, the President is issuing an Executive Order that will:

• Integrate Women’s Health Across the Federal Research Portfolio . The Executive Order directs the Initiative’s constituent agencies to develop and strengthen research and data standards on women’s health across all relevant research and funding opportunities, with the goal of helping ensure that the Administration is better leveraging every dollar of federal funding for health research to improve women’s health. These actions will build on the NIH’s current policy to ensure that research it funds considers women’s health in the development of study design and in data collection and analysis. Agencies will take action to ensure women’s health is being considered at every step in the research process—from the applications that prospective grantees submit to the way that they report on grant implementation.
• Prioritize Investments in Women’s Health Research . The Executive Order directs the Initiative’s constituent agencies to prioritize funding for women’s health research and encourage innovation in women’s health, including through ARPA-H and multi-agency initiatives such as the Small Business Innovation Research Program and the Small Business Technology Transfer Program. These entities are dedicated to high-impact research and innovation, including through the support of early-stage small businesses and entrepreneurs engaged in research and innovation. The Executive Order further directs HHS and NSF to study ways to leverage artificial intelligence to advance women’s health research. These additional investments—across a wide range of agencies—will support innovation and open new doors to breakthroughs in women’s health.
• Galvanize New Research on Women’s Midlife Health .  To narrow research gaps on diseases and conditions associated with women’s midlife health or that are more likely to occur after menopause, such as rheumatoid arthritis, heart attack, and osteoporosis, the President is directing HHS to: expand data collection efforts related to women’s midlife health; launch a comprehensive research agenda that will guide future investments in menopause-related research; identify ways to improve management of menopause-related issues and the clinical care that women receive; and develop new resources to help women better understand their options for menopause-related symptoms prevention and treatment. The Executive Order also directs the DoD and VA to study and take steps to improve the treatment of, and research related to, menopause for Service women and women veterans.
• Assess Unmet Needs to Support Women’s Health Research . The Executive Order directs the Office of Management and Budget and the Gender Policy Council to lead a robust effort to assess gaps in federal funding for women’s health research and identify changes—whether statutory, regulatory, or budgetary—that are needed to maximally support the broad scope of women’s health research across the federal government. Agencies will also be required to report annually on their investments in women’s health research, as well as progress towards their efforts to improve women’s health.

Today, agencies are also announcing new actions they are taking to promote women’s health research , as part of their ongoing efforts through the White House Initiative on Women’s Health Research. Agencies are announcing actions to:

Prioritize and Increase Investments in Women’s Health Research

• Launch an NIH-Cross Cutting Effort to Transform Women’s Health Throughout the Lifespan. NIH is launching an NIH-wide effort to close gaps in women’s health research across the lifespan. This effort—which will initially be supported by $200 million from NIH beginning in FY 2025—will allow NIH to catalyze interdisciplinary research, particularly on issues that cut across the traditional mandates of the institutes and centers at NIH. It will also allow NIH to launch ambitious, multi-faceted research projects such as research on the impact of perimenopause and menopause on heart health, brain health and bone health. In addition, the President’s FY25 Budget Request would double current funding for the NIH Office of Research on Women’s Health to support new and existing initiatives that emphasize women’s health research.

This coordinated, NIH-wide effort will be co-chaired by the NIH Office of the Director, the Office of Research on Women’s Health, and the institute directors from the National Institute on Aging; the National Heart, Lung, and Blood Institute; the National Institute on Drug Abuse; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute on Arthritis, Musculoskeletal and Skin Diseases.

• Invest in Research on a Wide Range of Women’s Health Issues. The bipartisan Congressionally Directed Medical Research Program (CDMRP), led out of DoD, funds research on women’s health encompassing a range of diseases and conditions that affect women uniquely, disproportionately, or differently from men. While the programs and topic areas directed by Congress differ each year, CDMRP has consistently funded research to advance women’s health since its creation in 1993. In Fiscal Year 2022, DoD implemented nearly $490 million in CDMRP investments towards women’s health research projects ranging from breast and ovarian cancer to lupus to orthotics and prosthetics in women.  In Fiscal Year 2023, DoD anticipates implementing approximately $500 million in CDMRP funding for women’s health research, including in endometriosis, rheumatoid arthritis, and chronic fatigue.
• Call for New Proposals on Emerging Women’s Health Issues . Today, NSF is calling for new research and education proposals to advance discoveries and innovations related to women’s health. To promote multidisciplinary solutions to women’s health disparities, NSF invites applications that would improve women’s health through a wide range of disciplines—from computational research to engineering biomechanics. This is the first time that NSF has broadly called for novel and transformative research that is focused entirely on women’s health topics, and proposals will be considered on an ongoing basis.
• Increase Research on How Environmental Factors Affect Women’s Health. The Environmental Protection Agency (EPA) is updating its grant solicitations and contracts to ensure that applicants prioritize, as appropriate, the consideration of women’s exposures and health outcomes. These changes will help ensure that women’s health is better accounted for across EPA’s research portfolio and increase our knowledge of women’s environmental health—from endocrine disruption to toxic exposure.
• Create a Dedicated, One-Stop Shop for NIH Funding Opportunities on Women’s Health. Researchers are often unaware of existing opportunities to apply for federal funding. To help close this gap, NIH is issuing a new Notice of Special Interest that identifies current, open funding opportunities related to women’s health research across a wide range of health conditions and all Institutes, Centers, and Offices. The NIH Office of Research on Women’s Health will build on this new Notice by creating a dedicated one-stop shop on open funding opportunities related to women’s health research. This will make it easier for researchers and institutions to find and apply for funding—instead of having to search across each of NIH’s 27 institutes for funding opportunities.

Foster Innovation and Discovery in Women’s Health

• Accelerate Transformative Research and Development in Women’s Health. ARPA-H’s Sprint for Women’s Health launched in February 2024 commits $100 million to transformative research and development in women’s health. ARPA-H is soliciting ideas for novel groundbreaking research and development to address women’s health, as well as opportunities to accelerate and scale tools, products, and platforms with the potential for commercialization to improve women’s health outcomes.
• Support Private Sector Innovation Through Additional Federal Investments in Women’s Health Research. The NIH’s competitive Small Business Innovation Research Program and the Small Business Technology Transfer Program is committing to further increasing—by 50 percent—its investments in supporting innovators and early-stage small businesses engaged in research and development on women’s health. These programs will solicit new proposals on promising women’s health innovation and make evidence-based investments that bridge the gap between performance of basic science and commercialization of resulting innovations. This commitment for additional funds builds on the investments the Administration has already made to increase innovation in women’s health through small businesses, including by increasing investments by sevenfold between Fiscal Year 2021 and Fiscal Year 2023.
• Advance Initiatives to Protect and Promote the Health of Women. The Food and Drug Administration (FDA) seeks to advance efforts to help address gaps in research and availability of products for diseases and conditions that primarily impact women, or for which scientific considerations may be different for women, and is committed to research and regulatory initiatives that facilitate the development of safe and effective medical products for women. FDA also plans to issue guidance for industry that relates to the inclusion of women in clinical trials and conduct outreach to stakeholders to discuss opportunities to advance women’s health across the lifespan. And FDA’s Office of Women’s Health will update FDA’s framework for women’s health research and seek to fund research with an emphasis on bridging gaps in knowledge on important women’s health topics, including sex differences and conditions that uniquely or disproportionately impact women.
• Use Biomarkers to Improve the Health of Women Through Early Detection and Treatment of Conditions, such as Endometriosis. NIH will launch a new initiative dedicated to research on biomarker discovery and validation to help improve our ability to prevent, diagnose, and treat conditions that affect women uniquely, including endometriosis. This NIH initiative will accelerate our ability to identify new pathways for diagnosis and treatment by encouraging multi-sector collaboration and synergistic research that will speed the transfer of knowledge from bench to bedside.
• Leverage Engineering Research to Improve Women’s Health . The NSF Engineering Research Visioning Alliance (ERVA) is convening national experts to identify high-impact research opportunities in engineering that can improve women’s health. ERVA’s Transforming Women’s Health Outcomes Through Engineering visioning event will be held in June 2024, and will bring together experts from across engineering—including those in microfluidics, computational modeling, artificial intelligence/imaging, and diagnostic technologies and devices—to evaluate the landscape for new applications in women’s health. Following this event, ERVA will issue a report and roadmap on critical areas where engineering research can impact women’s health across the lifespan.
• Drive Engineering Innovations in Women’s Health Discovery . NSF awardees at Texas A&M University will hold a conference in summer 2024 to collectively identify challenges and opportunities in improving women’s health through engineering. Biomedical engineers and scientists will explore and identify how various types of engineering tools, including biomechanics and immuno-engineering, can be applied to women’s health and spark promising new research directions.

Expand and Leverage Data Collection and Analysis Related to Women’s Health

• Help Standardize Data to Support Research on Women’s Health. NIH is launching an effort to identify and develop new common data elements related to women’s health that will help researchers share and combine datasets, promote interoperability, and improve the accuracy of datasets when it comes to women’s health. NIH will initiate this process by convening data and scientific experts across the federal government to solicit feedback on the need to develop new NIH-endorsed common data elements—which are widely used in both research and clinical settings. By advancing new tools to capture more data about women’s health, NIH will give researchers and clinicians the tools they need to enable more meaningful data collection, analysis, and reporting and comprehensively improve our knowledge of women’s health.
• Reflect Women’s Health Needs in National Coverage Determinations. The Centers for Medicare & Medicaid Services (CMS) will strengthen its review process, including through Coverage with Evidence Development guidance, to ensure that new medical services and technologies work well in women, as applicable, before being covered nationally through the Medicare program. This will help ensure that Medicare funds are used for treatments with a sufficient evidence base to show that they actually work in women, who make up more than half of the Medicare population.
• Leverage Data and Quality Measures to Advance Women’s Health Research. The Centers for Disease Control and Prevention (CDC) and the Health Resources and Services Administration (HRSA) are building on existing datasets to improve the collection, analysis, and reporting of information on women’s health. The CDC is expanding the collection of key quality measures across a woman’s lifespan, including to understand the link between pregnancy and post-partum hypertension and heart disease, and plans to release the Million Hearts Hypertension in Pregnancy Change Package. This resource will feature a menu of evidence-informed strategies by which clinicians can change care processes. Each strategy includes tested tools and resources to support related clinical quality improvement. HRSA is modernizing its Uniform Data System in ways that will improve the ability to assess how women are being served through HRSA-funded health centers. By improving the ability to analyze data on key clinical quality measures, CDC and HRSA can help close gaps in women’s health care access and identify new opportunities for high-impact research.  

Strengthen Coordination, Infrastructure, and Training to Support Women’s Health Research

• Launch New Joint Collaborative to Improve Women’s Health Research for Service Members and Veterans. DoD and VA are launching a new Women’s Health Research collaborative to explore opportunities that further promote joint efforts to advance women’s health research and improve evidence-based care for Service members and veterans. The collaborative will increase coordination with the goal of helping improve care across the lifespan for women in the military and women veterans. The Departments will further advance research on key women’s health issues and develop a roadmap to close pressing research gaps, including those specifically affecting Service women and women veterans.
• Coordinate Research to Advance the Health of Women in the Military. DoD will invest $10 million, contingent on available funds, in the Military Women’s Health Research Partnership. This Partnership is led by the Uniformed Services University and advances and coordinates women’s health research across the Department. The Partnership is supporting research in a wide range of health issues affecting women in the military, including cancers, mental and behavioral health, and the unique health care needs of Active Duty Service Women. In addition, the Uniformed Services University established a dedicated Director of Military Women’s Health Research Program, a role that is responsible for identifying research gaps, fostering collaboration, and coordinating and aligning a unified approach to address the evolving needs of Active Duty Service Women.
• Support EPA-Wide Research and Dissemination of Data on Women’s Health. EPA is establishing a Women’s Health Community of Practice to coordinate research and data dissemination. EPA also plans to direct the Board of Scientific Counselors to identify ways to advance EPA’s research with specific consideration of the intersection of environmental factors and women’s health, including maternal health.
• Expand Fellowship Training in Women’s Health Research. CDC, in collaboration with the CDC Foundation and American Board of Obstetrics and Gynecology, is expanding training in women’s health research and public health surveillance to OBGYNs, nurses and advanced practice nurses. Through fellowships and public health experiences with CDC, these clinicians will gain public health research skills to improve the health of women and children exposed to or affected by infectious diseases, mental health and substance use disorders. CDC will invite early career clinicians to train in public health and policy to become future leaders in women’s health research.

Improve Women’s Health Across the Lifespan

• Create a Comprehensive Research Agenda on Menopause. To help women get the answers they need about menopause, NIH will launch its first-ever Pathways to Prevention series on menopause and the treatment of menopausal symptoms. Pathways to Prevention is an independent, evidence-based process to synthesize the current state of the evidence, identify gaps in existing research, and develop a roadmap that can be used to help guide the field forward. The report, once completed, will help guide innovation and investments in menopause-related research and care across the federal government and research community.
• Improve Primary Care and Preventive Services for Women . The Agency for Healthcare Research and Quality (AHRQ) will issue a Notice of Intent to publish a funding opportunity announcement for research to advance the science of primary care, which will include a focus on women’s health. Through this funding opportunity, AHRQ will build evidence about key elements of primary care that influence patient outcomes and advance health equity—focusing on women of color—such as care coordination, continuity of care, comprehensiveness of care, person-centered care, and trust. The results from the funding opportunity will shed light on vital targets for improvements in the delivery of primary healthcare across a woman’s lifespan, including women’s health preventive services, prevention and management of multiple chronic diseases, perinatal care, transition from pediatric to adult care, sexual and reproductive health, and care of older adults.
• Promote the Health of American Indian and Alaska Native Women. The Indian Health Service is launching a series of engagements, including focus groups, to better understand tribal beliefs related to menopause in American Indian and Alaska Native Women. This series will inform new opportunities to expand culturally informed patient care and research as well as the development of new resources and educational materials.
• Connect Research to Real-World Outcomes to Improve Women’s Mental and Behavioral Health. The Substance Abuse and Mental Health Services Administration (SAMHSA) is supporting a range of health care providers to address the unique needs of women with or at risk for mental health and substance use disorders. Building on its current efforts to provide technical assistance through various initiatives , SAMHSA intends, contingent on available funds, to launch a new comprehensive Women’s Behavioral Health Technical Assistance Center. This center will identify and improve the implementation of best practices in women’s behavioral health across the life span; identify and fill critical gaps in knowledge of and resources for women’s behavioral health; and provide learning opportunities, training, and technical assistance for healthcare providers.
• Support Research on Maternal Health Outcomes. USDA will fund research to help recognize early warning signs of maternal morbidity and mortality in recipients of Special Supplemental Nutrition Program for Women, Infants, and Children (WIC), and anticipates awarding up to $5 million in Fiscal Year 2023 to support maternal health research through WIC. In addition, research being conducted through the Agricultural Research Service’s Human Nutrition Research Centers is focusing on women’s health across the lifespan, including the nutritional needs of pregnant and breastfeeding women and older adults.

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Use of Abortion Pills Has Risen Significantly Post Roe, Research Shows

By Pam Belluck

Pam Belluck has been reporting about reproductive health for over a decade.

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On the eve of oral arguments in a Supreme Court case that could affect future access to abortion pills, new research shows the fast-growing use of medication abortion nationally and the many ways women have obtained access to the method since Roe v. Wade was overturned in June 2022.

The Details

A study, published on Monday in the medical journal JAMA , found that the number of abortions using pills obtained outside the formal health system soared in the six months after the national right to abortion was overturned. Another report, published last week by the Guttmacher Institute , a research organization that supports abortion rights, found that medication abortions now account for nearly two-thirds of all abortions provided by the country’s formal health system, which includes clinics and telemedicine abortion services.

The JAMA study evaluated data from overseas telemedicine organizations, online vendors and networks of community volunteers that generally obtain pills from outside the United States. Before Roe was overturned, these avenues provided abortion pills to about 1,400 women per month, but in the six months afterward, the average jumped to 5,900 per month, the study reported.

Overall, the study found that while abortions in the formal health care system declined by about 32,000 from July through December 2022, much of that decline was offset by about 26,000 medication abortions from pills provided by sources outside the formal health system.

“We see what we see elsewhere in the world in the U.S. — that when anti-abortion laws go into effect, oftentimes outside of the formal health care setting is where people look, and the locus of care gets shifted,” said Dr. Abigail Aiken, who is an associate professor at the University of Texas at Austin and the lead author of the JAMA study.

The co-authors were a statistics professor at the university; the founder of Aid Access, a Europe-based organization that helped pioneer telemedicine abortion in the United States; and a leader of Plan C, an organization that provides consumers with information about medication abortion. Before publication, the study went through the rigorous peer review process required by a major medical journal.

The telemedicine organizations in the study evaluated prospective patients using written medical questionnaires, issued prescriptions from doctors who were typically in Europe and had pills shipped from pharmacies in India, generally charging about $100. Community networks typically asked for some information about the pregnancy and either delivered or mailed pills with detailed instructions, often for free.

Online vendors, which supplied a small percentage of the pills in the study and charged between $39 and $470, generally did not ask for women’s medical history and shipped the pills with the least detailed instructions. Vendors in the study were vetted by Plan C and found to be providing genuine abortion pills, Dr. Aiken said.

The Guttmacher report, focusing on the formal health care system, included data from clinics and telemedicine abortion services within the United States that provided abortion to patients who lived in or traveled to states with legal abortion between January and December 2023.

It found that pills accounted for 63 percent of those abortions, up from 53 percent in 2020. The total number of abortions in the report was over a million for the first time in more than a decade.

Why This Matters

Overall, the new reports suggest how rapidly the provision of abortion has adjusted amid post-Roe abortion bans in 14 states and tight restrictions in others.

The numbers may be an undercount and do not reflect the most recent shift: shield laws in six states allowing abortion providers to prescribe and mail pills to tens of thousands of women in states with bans without requiring them to travel. Since last summer, for example, Aid Access has stopped shipping medication from overseas and operating outside the formal health system; it is instead mailing pills to states with bans from within the United States with the protection of shield laws.

What’s Next

In the case that will be argued before the Supreme Court on Tuesday, the plaintiffs, who oppose abortion, are suing the Food and Drug Administration, seeking to block or drastically limit the availability of mifepristone, the first pill in the two-drug medication abortion regimen.

The JAMA study suggests that such a ruling could prompt more women to use avenues outside the formal American health care system, such as pills from other countries.

“There’s so many unknowns about what will happen with the decision,” Dr. Aiken said.

She added: “It’s possible that a decision by the Supreme Court in favor of the plaintiffs could have a knock-on effect where more people are looking to access outside the formal health care setting, either because they’re worried that access is going away or they’re having more trouble accessing the medications.”

Pam Belluck is a health and science reporter, covering a range of subjects, including reproductive health, long Covid, brain science, neurological disorders, mental health and genetics. More about Pam Belluck

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Founded in 1906 in the city of Moscow, Pirogov Medical University—officially known as Russian National Research Medical University named after N. I. Pirogov— is one of the oldest medical universities in Russia.  The first lecture took place on September 26, 1906, with 206 students, and the first graduation ceremony was celebrated in 1912. The University claims to be the first university in Russia that started offering medical education to women in the Russian Federation.It independently carries out various research projects in medicine and has received the status of National Research University in 2010.The Library of Pirogov Medical University has a collection of more than 7,50,000 books. For world-class clinical training and diverse practical exposure, the University collaborates with more 120 hospitals across the city of Moscow. Pirogov Medical University started accepting international students in 1959. Presently, more than 8,000 students are studying medicine at the University, out of which about 700 are international students.  The University has a strong team of about 2,000 faculty members. Pirogov Medical University is approved by the Medical Council of India (MCI) and offers a 6-Year Program for MBBS in Russia. Students in India, who have qualified NEET, can apply for direct admission to the MBBS Program of Pirogov Medical University.

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Foundation for Advancement of International Medical Education and Research (FAIMER)

To get admission to the MBBS Program of Pirogov Medical University, the student must qualify NEET-UG (National Eligibility cum Entrance Test-Undergraduate). 

Besides NEET-UG, there is no requirement to go through any additional entrance examination.

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• Pirogov Medical University was founded in 1906 in the Moscow city of Russia.
• In 1930, Pirogov Medical University organized the World’s first pediatric faculty.
• In 1963, Pirogov Medical University organized the World’s first biomedical faculty.
• In 2010, Pirogov Medical University received the status of National Research University.
• Presently, more than 8,000 students are studying at Pirogov Medical University, out of which about 700 are international students.

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Mbbs program, admission & support, medical licensing examination support, student life.

Founded in 1906 in the city of Moscow, Pirogov Medical University—officially known as Russian National Research Medical University named after N. I. Pirogov— is one of the oldest medical universities in Russia.  The first lecture took place on September 26, 1906, with 206 students, and the first graduation ceremony was celebrated in 1912. 

Focused on constantly improving the quality of education, the University entered the list of Times Higher Education World University Rankings and QS World University Rankings in 2019. 

The University claims to be the first university in Russia that started offering medical education to women in the Russian Federation. Among all milestones achieved by the University, two most celebrated achievements are that Pirogov Medical University created the world’s first pediatric faculty in 1930 and the world’s first biomedical faculty in 1963.

To provide students and visitors a glimpse into the decades of the glorious history of the University, Museum of the History of Pirogov Medical University was established in 1981, which continues to capture astonishing achievements of the University, its students, and members.

The University maintains a leading position in Russia by actively participating in activities of medical research and healthcare and delivering excellence in medical education and care. 

The University independently carries out various research projects in medicine and has received the status of National Research University in 2010. Conducting pre-clinical as well as clinical studies for a better understanding of human diseases, new medicines, and medical devices have been the center of research at Pirogov Medical University.  

To keep the students and healthcare professionals updated on the latest research and innovations in medicine, the University publishes its own scientific journal with articles on biomedical sciences and clinical medicine.

The Library of Pirogov Medical University has a collection of more than 7,50,000 books. Students can also access scientific journals and eBooks through the electronic library system. In collaboration with other universities, academic mobility and exchange programs are also arranged for students to help them get experience in other institutions and build new connections.

For the healthcare of locals, the University operates clinical centers in Moscow. Students are provided hands-on clinical training in these University-operated clinics and also involved in various clinical studies. For world-class training and diverse practical exposure, the University collaborates with more 120 hospitals across the city of Moscow.

Pirogov Medical University started accepting international students in 1959. Until now, the University has trained more than 80,000 doctors. Presently, more than 8,000 students are studying medicine at the University, out of which about 700 are international students.  The University has a strong team of about 2,000 faculty members.

Pirogov Medical University is listed in the World Directory of Medical Schools (WDOMS) and certified by the Educational Commission for Foreign Medical Graduates (ECFMG), United States of America. Pirogov Medical University is also approved by the Medical Council of Canada (MCC) and the Medical Council of India (MCI). The University offers a 6-Year Program for MBBS in Russia for local as well as international medical aspirants. Students in India, who have qualified NEET, can apply for direct admission to the MBBS Program of Pirogov Medical University.

Pirogov Medical University Faculty of Medicine 1 Ostrovityanov Str Moscow, 117997 Russian Federation

Pirogov Medical University offers a 6-Year MBBS Program in the Russian language. For international students, classes for initial years may be organized in English medium.

The Program for MBBS in Russia is focused on building a strong academic base with a pragmatic approach to education and medical research. To provide hands-on clinical experience, the students studying MBBS in Russia are involved in clinical training from the second year of MBBS. While education in classrooms and laboratories helps the students develop academic skills and sound theoretical understanding, clinical training in University-affiliated hospitals help them apply their knowledge into practice.

To get admission to the MBBS Program of Pirogov Medical University, you can apply online at Rus Education website.

Rus Education is duly authorized by the Russian Centre for Science and Culture (Cultural Department of The Embassy of the Russian Federation in India) to promote Russian Education among Indian Citizens. Rus Education is also an authorized associate of Pirogov Medical University. We facilitate one-window admission to the MBBS Program of Pirogov Medical University with no requirement of any donation or capitation and without any entrance examination.

Pirogov Medical University offers a healthy student life and an opportunity to experience life in Moscow, the capital city of Russia, and also the most vibrant and exciting location in the largest country in the world! 

For affordable accommodation of students and make their living experience safe and better, the University maintains a comfortable dormitory. Every room is shared by two or three students, and each floor has a shared kitchen where students can cook their food. Members of the dormitory help the newcomers to settle in their new homes. For the safety of the students, the University’s security team maintains 24-hour surveillance and is capable of providing emergency response, if required.

To help students adjust to life at university, it has a dedicated Student Support System in place. Every group of new students is assigned to two professors who guide the students not only about studying but about living as well, helping students adjust to the new environment and feel comfortable.

To keep students fit and active, Sports Center on the campus is equipped with facilities to play various sports, including badminton, basketball, volleyball, table tennis, swimming, football, hockey, chess, etc. Student can unleash their creativity by indulging in extracurricular adventures offered by Student Organizations and Societies. On the campus, there are ample opportunities for self-improvement and taking part in music, dance, sports competitions, and theater. 

For peer support, the University has a Student Council in place which offers support in academic as well as non-academic matters making student life stress free.

For the social upliftment and help students connect with the society and local people, they are involved in community and welfare organized by the University, including medical outreach, health awareness programs, and blood donation camps.  The University Volunteer Center organizes a number of volunteer activities to help students contribute to social causes.

Living in Moscow, students can explore its cultural heritage, museums, historic buildings, the world-famous Alexander Garden, and much more. For traveling in Moscow, students don’t face any problems, thanks to its convenient and cheap transportation system, especially the Moscow Metro.

With the charm of Moscow and all the student facilities and support services offered by the University, student life at Pirogov Medical University is a delight.

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©2024-25 Rus Education.

[ORGANIZATION OF MEDICAL CARE FOR CHILDREN WITH A NEW CORONAVIRUS INFECTION IN PATIENT CONDITIONS ON THE EXAMPLE OF THE CHILDREN'S CITY CLINICAL HOSPITAL NAMED AFTER Z. A. BASHLYAEVA]

Affiliations.

• 1 Children's City Clinical Hospital named after Z. A. Bashlyaeva of the Moscow City Health Department, 125373, Moscow, Russian Federation.
• 2 Pirogov Russian National Research Medical University, 117997, Moscow, Russian Federation.
• 3 Russian Medical Academy of Continuous Professional Education of the Ministry of Healthcare of the Russian Federation, 125993, Moscow, Russian Federation.
• 4 Pirogov Russian National Research Medical University, 117997, Moscow, Russian Federation, [email protected].
• 5 Research Institute for Healthcare Organization and Medical Management of Moscow Healthcare Department, 115088, Moscow, Russian Federation.
• PMID: 34792888
• DOI: 10.32687/0869-866X-2021-29-s2-1343-1349

The article presents an analysis of the work of the largest children's COVID-19 center in Moscow, organized on the basis of the Children's City Clinical Hospital named after Z. A. Bashlyaeva of the Moscow City Health Department. From March to November 2020 at the COVID-19 Center were hospitalized 2,837 patients with suspected/confirmed diagnosis of COVID-19, in total in 2020 1,876 children with a confirmed diagnosis of COVID-19 were treated, 58 (3%) children were in serious condition in the intensive care unit, of which children 11-18 years old were 25%. At the 2020 neonatal COVID-19 center, 215 newborns were observed with suspected COVID-19 diagnosis. The diagnosis of COVID-19 was confirmed in 18 children, while 8 newborns came from the home of COVID-19. In the Center for rehabilitation, where children aged 0 to 3 years old who were born with very low and extremely low body weight are observed, dispensary observation for children who have undergone COVID-19 is organized. 45 children who were observed fell ill with the new coronavirus infection. There were no deaths among children with COVID-19.

Keywords: COVID-19; COVID-center; children; new coronavirus infection; newborns; treatment.

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News releases.

News Release

Monday, March 18, 2024

NIH studies find severe symptoms of “Havana Syndrome,” but no evidence of MRI-detectable brain injury or biological abnormalities

Compared to healthy volunteers, affected U.S. government personnel did not exhibit differences that would explain symptoms.

Using advanced imaging techniques and in-depth clinical assessments, a research team at the National Institutes of Health (NIH) found no significant evidence of MRI-detectable brain injury, nor differences in most clinical measures compared to controls, among a group of federal employees who experienced anomalous health incidents (AHIs). These incidents, including hearing noise and experiencing head pressure followed by headache, dizziness, cognitive dysfunction and other symptoms, have been described in the news media as “Havana Syndrome” since U.S. government personnel stationed in Havana first reported the incidents. Scientists at the NIH Clinical Center conducted the research over the course of nearly five years and published their findings in two papers in JAMA today.

“Our goal was to conduct thorough, objective and reproducible evaluations to see if we could identify structural brain or biological differences in people who reported AHIs,” said Leighton Chan, M.D., chief, rehabilitation medicine and acting chief scientific officer, NIH Clinical Center, and lead author on one of the papers. “While we did not identify significant differences in participants with AHIs, it’s important to acknowledge that these symptoms are very real, cause significant disruption in the lives of those affected and can be quite prolonged, disabling and difficult to treat.”

Researchers designed multiple methods to evaluate more than 80 U.S. government employees and their adult family members, mostly stationed abroad, who had reported an AHI and compared them to matched healthy controls. The control groups included healthy volunteers who had similar work assignments but did not report AHIs. In this study, participants underwent a battery of clinical, auditory, balance, visual, neuropsychological and blood biomarkers testing. In addition, they received different types of MRI scans aimed at investigating volume, structure and function of the brain.

In this study, researchers obtained multiple measurements and used several methods and models to analyze the data. This was done to ensure the findings were highly reproducible, meaning similar results were found regardless of how many times participants were evaluated or their data statistically analyzed. Scientists also used deep phenotyping, which is an analysis of observable traits or biochemical characteristics of an individual, to assess any correlations between clinically reported symptoms and neuroimaging findings.

For the imaging portion of the study, participants underwent MRI scans an average of 80 days following symptom onset, although some participants had an MRI as soon as 14 days after reporting an AHI. Using thorough and robust methodology, which resulted in highly reproducible MRI metrics, the researchers were unable to identify a consistent set of imaging abnormalities that might differentiate participants with AHIs from controls.

“A lack of evidence for an MRI-detectable difference between individuals with AHIs and controls does not exclude that an adverse event impacting the brain occurred at the time of the AHI,” said Carlo Pierpaoli, M.D., Ph.D., senior investigator and chief of the Laboratory on Quantitative Medical Imaging at the National Institute of Biomedical Imaging and Bioengineering, part of NIH, and lead author on the neuroimaging paper. “It is possible that individuals with an AHI may be experiencing the results of an event that led to their symptoms, but the injury did not produce the long-term neuroimaging changes that are typically observed after severe trauma or stroke. We hope these results will alleviate concerns about AHI being associated with severe neurodegenerative changes in the brain.”

Similarly, there were no significant differences between individuals reporting AHIs and matched controls with respect to most clinical, research and biomarker measures, except for certain self-reported measures. Compared to controls, participants with AHIs self-reported significantly increased symptoms of fatigue, post-traumatic stress and depression. Forty-one percent of participants in the AHI group, from nearly every geographic area, met the criteria for functional neurological disorders (FNDs), a group of common neurological movement disorders caused by an abnormality in how the brain functions, or had significant somatic symptoms. FNDs can be associated with depression and anxiety, and high stress. Most of the AHI group with FND met specific criteria to enable the diagnosis of persistent postural-perceptual dizziness, also known as PPPD. Symptoms of PPPD include dizziness, non-spinning vertigo and fluctuating unsteadiness provoked by environmental or social stimuli that cannot be explained by some other neurologic disorder.

“The post-traumatic stress and mood symptoms reported are not surprising given the ongoing concerns of many of the participants,” said Louis French, Psy.D., neuropsychologist and deputy director of the National Intrepid Center of Excellence at Walter Reed National Military Medical Center and a co-investigator on the study. “Often these individuals have had significant disruption to their lives and continue to have concerns about their health and their future. This level of stress can have significant negative impacts on the recovery process.”

The researchers note that if the symptoms were caused by some external phenomenon, they are without persistent or detectable patho-physiologic changes. Additionally, it is possible that the physiologic markers of an external phenomenon are no longer detectable or cannot be identified with the current methodologies and sample size.

About the NIH Clinical Center: The NIH Clinical Center is the clinical research hospital for the National Institutes of Health. Through clinical research, clinician-investigators translate laboratory discoveries into better treatments, therapies and interventions to improve the nation's health. More information: https://clinicalcenter.nih.gov .

About the National Institute of Biomedical Imaging and Bioengineering (NIBIB): NIBIB’s mission is to improve health by leading the development and accelerating the application of biomedical technologies. The Institute is committed to integrating the physical and engineering sciences with the life sciences to advance basic research and medical care. NIBIB supports emerging technology research and development within its internal laboratories and through grants, collaborations, and training. More information is available at the NIBIB website: https://www.nibib.nih.gov .

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov .

NIH…Turning Discovery Into Health ®

Pierpaoli C, Nayak A, Hafiz R, et al. Neuroimaging Findings in United States Government Personnel and their Family Members Involved in Anomalous Health Incidents. JAMA. Published online March 18, 2024. doi: 10.1001/jama.2024.2424

Chan L, Hallett M, Zalewski C, et al. Clinical, Biomarker, and Research Tests Among United States Government Personnel and their Family Members Involved in Anomalous Health Incidents. JAMA. Published online March 10, 2024. doi: 10.1001/jama.2024.2413

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