current research in medicine

Current Research in Medicine

Aims and scope.

Current Research in Medicine is a peer-reviewed, open access international medical journal dedicated to publish and disseminate high-quality research/review articles on health and health care, general and internal medicine, pathogenesis, epidemiology, diagnosis, monitoring and treatment protocols.

Science Publications is pleased to announce the launch of a new open access journal, Journal of Adaptive Structures. JAS brings together emerging technologies for adaptive smart structures, including advanced materials, smart actuation, sensing and control, to pursue the progressive adoption of the major scientific achievements in this multidisciplinary field on-board of commercial aircraft.

It is with great pleasure that we announce the SGAMR Annual Awards 2020. This award is given annually to Researchers and Reviewers of International Journal of Structural Glass and Advanced Materials Research (SGAMR) who have shown innovative contributions and promising research as well as others who have excelled in their Editorial duties.

This special issue "Neuroinflammation and COVID-19" aims to provide a space for debate in the face of the growing evidence on the affectation of the nervous system by COVID-19, supported by original studies and case series.

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Nih research matters.

December 22, 2021

2021 Research Highlights — Promising Medical Findings

Results with potential for enhancing human health.

With NIH support, scientists across the United States and around the world conduct wide-ranging research to discover ways to enhance health, lengthen life, and reduce illness and disability. Groundbreaking NIH-funded research often receives top scientific honors. In 2021, these honors included Nobel Prizes to five NIH-supported scientists . Here’s just a small sample of the NIH-supported research accomplishments in 2021.

Printer-friendly version of full 2021 NIH Research Highlights

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Advancing COVID-19 treatment and prevention

Amid the sustained pandemic, researchers continued to develop new drugs and vaccines for COVID-19. They found oral drugs that could  inhibit virus replication in hamsters and shut down a key enzyme that the virus needs to replicate. Both drugs are currently in clinical trials. Another drug effectively treated both SARS-CoV-2 and RSV, another serious respiratory virus, in animals. Other researchers used an airway-on-a-chip to screen approved drugs for use against COVID-19. These studies identified oral drugs that could be administered outside of clinical settings. Such drugs could become powerful tools for fighting the ongoing pandemic. Also in development are an intranasal vaccine , which could help prevent virus transmission, and vaccines that can protect against a range of coronaviruses .

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Developments in Alzheimer’s disease research

One of the hallmarks of Alzheimer’s is an abnormal buildup of amyloid-beta protein. A study in mice suggests that antibody therapies targeting amyloid-beta protein could be more effective after enhancing the brain’s waste drainage system . In another study, irisin, an exercise-induced hormone, was found to improve cognitive performance in mice . New approaches also found two approved drugs (described below) with promise for treating AD. These findings point to potential strategies for treating Alzheimer’s. Meanwhile, researchers found that people who slept six hours or less per night in their 50s and 60s were more likely to develop dementia later in life, suggesting that inadequate sleep duration could increase dementia risk.

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New uses for old drugs

Developing new drugs can be costly, and the odds of success can be slim. So, some researchers have turned to repurposing drugs that are already approved for other conditions. Scientists found that two FDA-approved drugs were associated with lower rates of Alzheimer’s disease. One is used for high blood pressure and swelling. The other is FDA-approved to treat erectile dysfunction and pulmonary hypertension. Meanwhile, the antidepressant fluoxetine was associated with reduced risk of age-related macular degeneration. Clinical trials will be needed to confirm these drugs’ effects.

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Making a wireless, biodegradable pacemaker

Pacemakers are a vital part of medical care for many people with heart rhythm disorders. Temporary pacemakers currently use wires connected to a power source outside the body. Researchers developed a temporary pacemaker that is powered wirelessly. It also breaks down harmlessly in the body after use. Studies showed that the device can generate enough power to pace a human heart without causing damage or inflammation.

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Fungi may impair wound healing in Crohn’s disease

Inflammatory bowel disease develops when immune cells in the gut overreact to a perceived threat to the body. It’s thought that the microbiome plays a role in this process. Researchers found that a fungus called  Debaryomyces hansenii  impaired gut wound healing in mice and was also found in damaged gut tissue in people with Crohn’s disease, a type of inflammatory bowel disease. Blocking this microbe might encourage tissue repair in Crohn’s disease.

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Nanoparticle-based flu vaccine

Influenza, or flu, kills an estimated 290,000-650,000 people each year worldwide. The flu virus changes, or mutates, quickly. A single vaccine that conferred protection against a wide variety of strains would provide a major boost to global health. Researchers developed a nanoparticle-based vaccine that protected against a broad range of flu virus strains in animals. The vaccine may prevent flu more effectively than current seasonal vaccines. Researchers are planning a Phase 1 clinical trial to test the vaccine in people.

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A targeted antibiotic for treating Lyme disease

Lyme disease cases are becoming more frequent and widespread. Current treatment entails the use of broad-spectrum antibiotics. But these drugs can damage the patient’s gut microbiome and select for resistance in non-target bacteria. Researchers found that a neglected antibiotic called hygromycin A selectively kills the bacteria that cause Lyme disease. The antibiotic was able to treat Lyme disease in mice without disrupting the microbiome and could make an attractive therapeutic candidate.

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Retraining the brain to treat chronic pain

More than 25 million people in the U.S. live with chronic pain. After a treatment called pain reprocessing therapy, two-thirds of people with mild or moderate chronic back pain for which no physical cause could be found were mostly or completely pain-free. The findings suggest that people can learn to reduce the brain activity causing some types of chronic pain that occur in the absence of injury or persist after healing.

2021 Research Highlights — Basic Research Insights >>

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• Stem Cell Investig

Current state of stem cell-based therapies: an overview

Riham mohamed aly.

1 Department of Basic Dental Science, National Research Centre, Cairo, Egypt;

2 Stem Cell Laboratory, Center of Excellence for Advanced Sciences, National Research Centre, Cairo, Egypt

Recent research reporting successful translation of stem cell therapies to patients have enriched the hope that such regenerative strategies may one day become a treatment for a wide range of vexing diseases. In fact, the past few years witnessed, a rather exponential advancement in clinical trials revolving around stem cell-based therapies. Some of these trials resulted in remarkable impact on various diseases. In this review, the advances and challenges for the development of stem-cell-based therapies are described, with focus on the use of stem cells in dentistry in addition to the advances reached in regenerative treatment modalities in several diseases. The limitations of these treatments and ongoing challenges in the field are also discussed while shedding light on the ethical and regulatory challenges in translating autologous stem cell-based interventions, into safe and effective therapies.

Introduction

Cell-based therapy as a modality of regenerative medicine is considered one of the most promising disciplines in the fields of modern science & medicine. Such an advanced technology offers endless possibilities for transformative and potentially curative treatments for some of humanities most life threatening diseases. Regenerative medicine is rapidly becoming the next big thing in health care with the particular aim of repairing and possibly replacing diseased cells, tissues or organs and eventually retrieving normal function. Fortunately, the prospect of regenerative medicine as an alternative to conventional drug-based therapies is becoming a tangible reality by the day owing to the vigorous commitment of the research communities in studying the potential applications across a wide range of diseases like neurodegenerative diseases and diabetes, among many others ( 1 ).

Recent research reporting successful translation of stem cell therapies to patients have enriched the hope that such regenerative strategies may one day become a treatment for a wide range of vexing diseases ( 2 ). In fact, the past few years witnessed, a rather exponential advancement in clinical trials revolving around stem cell-based therapies. Some of these trials resulted in remarkable impact on various diseases ( 3 ). For example, a case of Epidermolysis Bullosa manifested signs of skin recovery after treatment with keratinocyte cultures of epidermal stem cells ( 4 ). Also, a major improvement in eyesight of patients suffering from macular degeneration was reported after transplantation of patient-derived induced pluripotent stem cells (iPSCs) that were induced to differentiate into pigment epithelial cells of the retina ( 5 ).

However, in spite of the increased amount of publications reporting successful cases of stem cell-based therapies, a major number of clinical trials have not yet acquired full regulatory approvals for validation as stem cell therapies. To date, the most established stem cell treatment is bone marrow transplants to treat blood and immune system disorders ( 1 , 6 , 7 ).

In this review, the advances and challenges for the development of stem-cell-based therapies are described, with focus on the use of stem cells in dentistry in addition to the advances reached in regenerative treatment modalities in several diseases. The limitations of these treatments and ongoing challenges in the field are also discussed while shedding light on the ethical and regulatory challenges in translating autologous stem cell-based interventions, into safe and effective therapies.

Stem cell-based therapies

Stem cell-based therapies are defined as any treatment for a disease or a medical condition that fundamentally involves the use of any type of viable human stem cells including embryonic stem cells (ESCs), iPSCs and adult stem cells for autologous and allogeneic therapies ( 8 ). Stem cells offer the perfect solution when there is a need for tissue and organ transplantation through their ability to differentiate into the specific cell types that are required for repair of diseased tissues.

However, the complexity of stem cell-based therapies often leads researchers to search for stable, safe and easily accessible stem cells source that has the potential to differentiate into several lineages. Thus, it is of utmost importance to carefully select the type of stem cells that is suitable for clinical application ( 7 , 9 ).

Stem cells hierarchy

There are mainly three types of stem cells. All three of them share the significant property of self-renewal in addition to a unique ability to differentiate. However, it should be noted that stem cells are not homogeneous, but rather exist in a developmental hierarchy ( 10 ). The most basic and undeveloped of stem cells are the totipotent stem cells. These cells are capable of developing into a complete embryo while forming the extra-embryonic tissue at the same time. This unique property is brief and starts with the fertilization of the ovum and ends when the embryo reaches the four to eight cells stage. Following that cells undergo subsequent divisions until reaching the blastocyst stage where they lose their totipotency property and assume a pluripotent identity where cells are only capable of differentiating into every embryonic germ layer (ectoderm, mesoderm and endoderm). Cells of this stage are termed “embryonic stem cells” and are obtained by isolation from the inner cell mass of the blastocyst in a process that involves the destruction of the forming embryo. After consecutive divisions, the property of pluripotency is lost and the differentiation capability becomes more lineage restricted where the cells become multipotent meaning that they can only differentiate into limited types of cells related to the tissue of origin. This is the property of “adult stem cells”, which helps create a state of homeostasis throughout the lifetime of the organism. Adult stem cells are present in a metabolically quiescent state in almost all specialized tissues of the body, which includes bone marrow and oral and dental tissues among many others ( 11 ).

Many authors consider adult stem cells the gold standard in stem cell-based therapies ( 12 , 13 ). Adult stem cells demonstrated signs of clinical success especially in hematopoietic transplants ( 14 , 15 ). In contrast to ESCs, adult stem cells are not subjected to controversial views regarding their origin. The fact that ESCs derivation involves destruction of human embryos renders them unacceptable for a significant proportion of the population for ethical and religious convictions ( 16 - 18 ).

Turning point in stem cell research

It was in 2006 when Shinya Yamanka achieved a scientific breakthrough in stem cell research by succeeding in generating cells that have the same properties and genetic profile of ESCs. This was achieved via the transient over-expression of a cocktail of four transcription factors; OCT4, SOX2, KLF4 and MYC in, fully differentiated somatic cells, namely fibroblasts ( 19 , 20 ). These cells were called iPSCs and has transformed the field of stem cell research ever since ( 21 ). The most important feature of these cells is their ability to differentiate into any of the germ layers just like ESCs precluding the ethical debate surrounding their use. The development of iPSCs technology has created an innovative way to both identify and treat diseases. Since they can be generated from the patient’s own cells, iPSCs thus present a promising potential for the production of pluripotent derived patient-matched cells that could be used for autologous transplantation. True these cells symbolize a paradigm shift since they enable researchers to directly observe and treat relevant patient cells; nevertheless, a number of challenges still need to be addressed before iPSCs-derived cells can be applied in cell therapies. Such challenges include; the detection and removal of incompletely differentiated cells, addressing the genomic and epigenetic alterations in the generated cells and overcoming the tumorigenicity of these cells that could arise on transplantation ( 22 ).

Therapeutic translation of stem cell research

With the rapid increase witnessed in stem cell basic research over the past years, the relatively new research discipline “Translational Research” has evolved significantly building up on the outcomes of basic research in order to develop new therapies. The clinical translation pathway starts after acquiring the suitable regulatory approvals. The importance of translational research lies in it’s a role as a filter to ensure that only safe and effective therapies reach the clinic ( 23 ). It bridges the gap from bench to bed. Currently, some stem cell-based therapies utilizing adult stem cells are clinically available and mainly include bone marrow transplants of hematopoietic stem cells and skin grafts for severe burns ( 23 ). To date, there are more than 3,000 trials involving the use of adult stem cells registered in WHO International Clinical Trials Registry. Additionally, initial trials involving the new and appealing iPSCs based therapies are also registered. In fact, the first clinical attempt employing iPSCs reported successful results in treating macular degeneration ( 24 ). Given the relative immaturity in the field of cellular therapy, the outcomes of such trials shall facilitate the understanding of the timeframes needed to achieve successful therapies and help in better understanding of the diseases. However, it is noteworthy that evaluation of stem cell-based therapies is not an easy task since transplantation of cells is ectopic and may result in tumor formation and other complications. This accounts for the variations in the results reported from previous reports. The following section discusses the published data of some of the most important clinical trials involving the use of different types of stem cells both in medicine and in dentistry.

Stem cell-based therapy for neurodegenerative diseases

The successful generation of neural cells from stem cells in vitro paved the way for the current stem cell-based clinical trials targeting neurodegenerative diseases ( 25 , 26 ). These therapies do not just target detaining the progression of irrecoverable neuro-degenerative diseases like Parkinson’s, Alzheimer’s, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), but are also focused on completely treating such disorders.

Parkinson’s disease (PD)

PD is characterized by a rapid loss of midbrain dopaminergic neurons. The first attempt for using human ESC cells to treat PD was via the generation of dopaminergic-like neurons, later human iPSCs was proposed as an alternative to overcome ESCs controversies ( 27 ). Both cells presented hope for obtaining an endless source of dopaminergic neurons instead of the previously used fetal brain tissues. Subsequently, protocols that mimicked the development of dopaminergic neurons succeeded in generating dopaminergic neurons similar to that of the midbrain which were able to survive, integrate and functionally mature in animal models of PD preclinically ( 28 ). Based on the research presented by different groups; the “Parkinson’s Global Force” was formed which aimed at guiding researchers to optimize their cell characterization and help promote the clinical progress toward successful therapy. Recently, In August 2018, Shinya Yamanka initiated the first approved clinical trial to treat PD using iPSCs. Seven patients suffering from moderate PD were recruited ( 29 ). Donor matched allogeneic cells were used to avoid any genetic influence of the disease. The strategy behind the trial involved the generation of dopaminergic progenitors followed by surgical transplantation into the brains of patients by a special device. In addition, immunosuppressant medications were given to avoid any adverse reaction. Preliminary results so far revealed the safety of the treatment.

MS is an inflammatory and neurodegenerative autoimmune disease of the central nervous system. Stem cell-based therapies are now exploring the possibility of halting the disease progression and reverse the neural damage. A registered phase 1 clinical trial was conducted by the company Celgene TM in 2014 using placental-derived mesenchymal stem cells (MSCs) infusion to treat patients suffering from MS ( 30 ). This trial was performed at 6 centers in the United States and 2 centers in Canada and included 16 patients. Results demonstrated that cellular infusions were safe with no signs of paradoxical aggravation. However, clinical responses from patients indicated that the cellular treatment did not improve the MS condition ( 31 ). For the last decade immunoablative therapy demonstrated accumulative evidence of inducing long-term remission and improvement of disability caused by MS. This approach involves the replacement of the diseased immune system through administration of high-dose immunosuppressive therapy followed by hematopoietic stem cells infusion ( 32 ). However, immunoablation strategies demonstrated several complications such as infertility and neurological disabilities. A number of randomized controlled trials are planned to address these concerns ( 32 ). Currently, new and innovative stem cell-based therapies for MS are only in the initial stages, and are based on different mechanisms exploring the possibility of replacing damaged neuronal tissue with neural cells derived from iPSCs however, the therapeutic potential of iPSCs is still under research ( 33 ).

ALS is a neurodegenerative disease that causes degeneration of the motor neurons which results in disturbance in muscle performance. The first attempt to treat ALS was through the transplantation of MSCs in a mouse model. The outcomes of this experiment were promising and resulted in a decrease of the disease manifestations and thus providing proof of principal ( 34 ). Based on these results, several planned/ongoing clinical trials are on the way. These trials mainly assess the safety of the proposed concept and have not proved clinical success to date. Notably, while pre-clinical studies have reported that cells derived from un-diseased individuals are superior to cells from ALS patients; most of the clinical trials attempted have employed autologous transplantation. This information may account for the absence of therapeutic improvement reported ( 35 ).

Spinal cord injury

Other neurologic indications for the use of stem cells are spinal cord injuries. Though the transplantation of different forms of neural stem cells and oligo-dendrocyte progenitors has led to growth in the axons in addition to neural connectivity which presents a possibility for repair ( 36 ), proof of recovered function has yet to be established in stringent clinical trials. Nevertheless, Japan has recently given approval to stem-cell treatment for spinal-cord injuries. This approval was based on clinical trials that are yet to be published and involves 13 patients, who are suffering from recent spinal-cord injury. The Japanese team discovered that injection of stem cells isolated from the patients’ bone marrow aided in regaining some lost sensation and mobility. This is the first stem cell-based therapy targeting spinal-cord injuries to gain governmental approval to offer to patients ( 37 ).

Stem cell-based therapies for ocular diseases

A huge number of the currently registered clinical trials for stem cell-based therapies target ocular diseases. This is mainly due to the fact that the eye is an immune privileged site. Most of these trials span various countries including Japan, China, Israel, Korea, UK, and USA and implement allogeneic ESC lines ( 35 , 36 ). Notably, the first clinical trial to implement the use autologous iPSCs-derived retinal cells was in Japan which followed the new regulatory laws issued in 2014 by Japan’s government to regulate regenerative medicine applications. Two patients were recruited in this trial, the first one received treatment for macular degeneration using iPSCs-generated retinal cell sheet ( 37 ). After 1 year of follow-up, there were no signs of serious complications including abnormal proliferation and systemic malignancy. Moreover, there were no signs of rejection of the transplanted retinal epithelial sheet in the second year follow-up. Most importantly, the signs of corrected visual acuity of the treated eye were reported. These results were enough to conclude that iPSCs-based autologous transplantation was safe and feasible ( 38 ). It is worthy to mention that the second patient was withdrawn from the study due to detectable genetic variations the patient’s iPSCs lines which was not originally present in the patient’s original fibroblasts. Such alterations may jeopardize the overall safety of the treatment. The fact that this decision was taken, even though the performed safety assays did not demonstrate tumorgenicity in the iPSCs-derived retinal pigment epithelium (RPE) cells, indicates that researchers in the field of iPSCs have full awareness of the importance of safety issues ( 39 ).

Stem cell-based therapies for treatment of diabetes

Pancreatic beta cells are destructed in type 1 diabetes mellitus, because of disorders in the immune system while in type 2 insulin insufficiency is caused by failure of the beta-cell to normally produce insulin. In both cases the affected cell is the beta cell, and since the pancreas does not efficiently regenerate islets from endogenous adult stem cells, other cell sources were tested ( 38 ). Pluripotent stem cells (PSCs) are considered the cells of choice for beta cell replacement strategies ( 39 ). Currently, there are a few industry-sponsored clinical trials that are registered targeting beta cell replacement using ESCs. These trials revolve around the engraftment of insulin-producing beta cells in an encapsulating device subcutaneously to protect the cells from autoimmunity in patients with type 1 diabetes ( 40 ). The company ViaCyte TM in California recently initiated a phase I/II trial ( {"type":"clinical-trial","attrs":{"text":"NCT02239354","term_id":"NCT02239354"}} NCT02239354 ) in 2014 in collaboration with Harvard University. This trial involves 40 patients and employs two subcutaneous capsules of insulin producing beta cells generated from ESCs. The results shall be interesting due to the ease of monitoring and recovery of the transplanted cells. The preclinical studies preceding this trial demonstrated successful glycemic correction and the devices were successfully retrieved after 174 days and contained viable insulin-producing cells ( 41 ).

Stem cells in dentistry

Stem cells have been successfully isolated from human teeth and were studied to test their ability to regenerate dental structures and periodontal tissues. MSCs were reported to be successfully isolated from dental tissues like dental pulp of permanent and deciduous teeth, periodontal ligament, apical papilla and dental follicle ( 42 - 44 ). These cells were described as an excellent cell source owing to their ease of accessibility, their ability to differentiate into osteoblasts and odontoblasts and lack of ethical controversies ( 45 ). Moreover, dental stem cells demonstrated superior abilities in immunomodulation properties either through cell to cell interaction or via a paracrine effect ( 46 ). Stem cells of non-dental origin were also suggested for dental tissue and bone regeneration. Different approaches were investigated for achieving dental and periodontal regeneration ( 47 ); however, assessments of stem cells after transplantation still require extensive studying. Clinical trials have only recently begun and their results are yet to be fully evaluated. However, by carefully applying the knowledge acquired from the extensive basic research in dental and periodontal regeneration, stem cell-based dental and periodontal regeneration may soon be a readily available treatment. To date, there are more than 6,000 clinical trials involving the use of with stem cells, however only a total of 44 registered clinical trials address oral diseases worldwide ( 48 ). Stem cell-based clinical trials with reported results targeting the treatment of oral disease are discussed below.

Dental pulp regeneration

The first human clinical study using autologous dental pulp stem cells (DPSCs) for complete pulp regeneration was reported by Nakashima et al. in 2017 ( 49 ). This pilot study was based on extensive preclinical studies conducted by the same group ( 50 ). Patients with irreversible pulpitis were recruited and followed up for 6 months following DPSCs’ transplantation. Granulocyte colony-stimulating factor was administered to induce stem cell mobilization to enrich the stem cell populations. The research team reported that the use of DPSCs seeded on collagen scaffold in molars and premolars undergoing pulpectomy was safe. No adverse events or toxicity were demonstrated in the clinical and laboratory evaluations. Positive electric pulp testing was obtained after cell transplantation in all patients. Moreover, magnetic resonance imaging of the de - novo tissues formed in the root canal demonstrated similar results to normal pulp, which indicated successful pulp regeneration. A different group conducted a clinical trial that recruited patients diagnosed with necrotic pulp. Autologous stem cells from deciduous teeth were employed to induce pulp regeneration ( 51 ). Follow-up of the cases after a year from the intervention reported evidence of pulp regeneration with vascular supply and innervation. In addition, no signs of adverse effects were observed in patients receiving DPSCs transplantation. Both trials are proceeding with the next phases, however the results obtained are promising.

Periodontal tissue regeneration

Aimetti et al. performed a study which included eleven patients suffering from chronic periodontitis and have one deep intra bony defect in addition to the presence of one vital tooth that needs extraction ( 52 ). Pulp tissue was passed through 50-µm filters in presence of collagen sponge scaffold and was followed by transplantation in the bony defects caused by periodontal disease. Both clinical and radiographic evaluations confirmed the efficacy of this therapeutic intervention. Periodontal examination, attachment level, and probe depth showed improved results in addition to significant stability of the gingival margin. Moreover, radiographic analysis demonstrated bone regeneration.

Regeneration of mandibular bony defects

The first clinical study using DPSCs for oro-maxillo-facial bone regeneration was conducted in 2009 ( 53 ). Patients in this study suffered from extreme bone loss following extraction of third molars. A bio-complex composed of DPSCs cultured on collagen sponge scaffolds was applied to the affected sites. Vertical repair of the damaged area with complete restoration of the periodontal tissue was demonstrated six months after the treatment. Three years later, the same group published a report evaluating the stability and quality of the regenerated bone after DPSCs transplantation ( 54 ). Histological and advanced holotomography demonstrated that newly formed bone was uniformly vascularized. However, it was of compact type, rather than a cancellous type which is usually the type of bone in this region.

Stem cells for treatment of Sjögren’s syndrome

Sjögren’s syndrome (SS) is a systemic autoimmune disease marked by dry mouth and eyes. A novel therapeutic approach for SS. utilizing the infusion of MSCs in 24 patients was reported by Xu et al. in 2012 ( 55 ). The strategy behind this treatment was based on the immunologic regulatory functions of MSCs. Infused MSCs migrated toward the inflammatory sites in a stromal cell-derived factor-1-dependent manner. Results reported from this clinical trial demonstrated suppressed autoimmunity with subsequent restoration of salivary gland secretion in SS patients.

Stem cells and tissue banks

The ability to bank autologous stem cells at their most potent state for later use is an essential adjuvant to stem cell-based therapies. In order to be considered valid, any novel stem cell-based therapy should be as effective as the routine treatment. Thus, when appraising a type of stem cells for application in cellular therapies, issues like immune rejection must be avoided and at the same time large numbers of stem cells must be readily available before clinical implementation. iPSCs theoretically possess the ability to proliferate unlimitedly which pose them as an attractive source for use in cell-based therapies. Unlike, adult stem cells iPSCs ability to propagate does not decrease with time ( 22 ). Recently, California Institute for Regenerative Medicine (CIRM) has inaugurated an iPSCs repository to provide researchers with versatile iPSCs cell lines in order to accelerate stem cell treatments through studying genetic variation and disease modeling. Another important source for stem cells banking is the umbilical cord. Umbilical cord is immediately cryopreserved after birth; which permits stem cells to be successfully stored and ready for use in cell-based therapies for incurable diseases of a given individuals. However, stem cells of human exfoliated deciduous teeth (SHEDs) are more attractive as a source for stem cell banking. These cells have the capacity to differentiate into further cell types than the rest of the adult stem cells ( 56 ). Moreover, procedures involving the isolation and cryopreservation of these cells are un-complicated and not aggressive. The most important advantage of banking SHEDs is the insured autologous transplant which avoids the possibility of immune rejection ( 57 ). Contrary to cord blood stem cells, SHEDs have the ability to differentiate into connective tissues, neural and dental tissues ( 58 ) Finally, the ultimate goal of stem cell banking, is to establish a repository of high-quality stem cell lines derived from many individuals for future use in therapy.

Current regulatory guidelines for stem cell-based therapies

With the increased number of clinical trials employing stem cells as therapeutic approaches, the need for developing regulatory guidelines and standards to ensure patients safety is becoming more and more essential. However, the fact that stem cell therapy is rather a new domain makes it subject to scientific, ethical and legal controversies that are yet to be regulated. Leading countries in the field have devised guidelines serving that purpose. Recently, the Food and Drug Administration (FDA) has released regulatory guidelines to ensure that these treatments are safe and effective ( 59 ). These guidelines state that; treatments involving stem cells that have been minimally manipulated and are intended for homogeneous use do not require premarket approval to come into action and shall only be subjected to regulatory guidelines against disease transmission. In 2014, a radical regulatory reform in Japan occurred with the passing of two new laws that permitted conditional approval of cell-based treatments following early phase clinical trials on the condition that clinical safety data are provided from at least ten patients. These laws allow skipping most of the traditional criteria of clinical trials in what was described as “fast track approvals” and treatments were classified according to risk ( 60 ). To date, the treatments that acquired conditional approval include those targeting; spinal-cord injury, cardiac disease and limb ischemia ( 61 ). Finally, regulatory authorities are now demanding application of standardization and safety regulations protocols for cellular products, which include the use of Xeno-free culture media, recombinant growth factors in addition to “Good Manufacturing Practice” (GMP) culture supplies.

Challenges & ethical issues facing stem cell-based therapies

Stem cell-based therapies face many obstacles that need to be urgently addressed. The most persistent concern is the ethical conflict regarding the use of ESCs. As previously mentioned, ESCs are far superior regarding their potency; however, their derivation requires destruction human embryos. True, the discovery of iPSCs overcame this concern; nevertheless, iPSCs themselves currently face another ethical controversy of their own which addresses their unlimited capacity of differentiation with concerns that these cells could one day be applied in human cloning. The use of iPSCs in therapy is still considered a high-risk treatment modality, since transplantation of these cells could induce tumor formation. Such challenge is currently addressed through developing optimized protocols to ensure their safety in addition to developing global clinical-grade iPSCs cell lines before these cells are available for clinical use ( 61 ). As for MSCs, these cells have been universally considered safe, however continuous monitoring and prolonged follow-up should be the focus of future research to avoid the possibility of tumor formation after treatments ( 62 ). Finally, it could be postulated that one of the most challenging ethical issues faced in the field of stem cell-based therapies at the moment, is the increasing number of clinics offering unproven stem cell-based treatments. Researchers are thus morally obligated to ensure that ethical considerations are not undermined in pursuit of progress in clinical translation.

Conclusions

Stem cell therapy is becoming a tangible reality by the day, thanks to the mounting research conducted over the past decade. With every research conducted the possibilities of stem cells applications increased in spite of the many challenges faced. Currently, progress in the field of stem cells is very promising with reports of clinical success in treating various diseases like; neurodegenerative diseases and macular degeneration progressing rapidly. iPSCs are conquering the field of stem cells research with endless possibilities of treating diseases using patients own cells. Regeneration of dental and periodontal tissues using MSCs has made its way to the clinic and soon enough will become a valid treatment. Although, challenges might seem daunting, stem cell research is advancing rapidly and cellular therapeutics is soon to be applicable. Fortunately, there are currently tremendous efforts exerted globally towards setting up regulatory guidelines and standards to ensure patients safety. In the near future, stem cell-based therapies shall significantly impact human health.

Acknowledgments

Funding: None.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/ .

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/sci-2020-001 ). The author has no conflicts of interest to declare.

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• Published: 07 December 2020

2021: research and medical trends in a post-pandemic world

• Mike May 1  

Nature Medicine volume  26 ,  pages 1808–1809 ( 2020 ) Cite this article

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Goodbye 2020, a year of arguably too many challenges for the world. As tempting as it is to leave this year behind, the biomedical community is forever changed by the pandemic, while business as usual needs to carry on. Looking forward to a new year, experts share six trends for the biomedical community in 2021.

Summing up 2020, Sharon Peacock, director of the COVID-19 Genomics UK Consortium, says “we’ve seen some excellent examples of people working together from academia, industry, and healthcare sectors...I’m hopeful that will stay with us going into 2021.” Nonetheless, we have lost ground and momentum in non-COVID research, she says. “This could have a profound effect on our ability to research other areas in the future.”

The coronavirus SARS-CoV-2 has already revealed weaknesses in medical research and clinical capabilities, as well as opportunities. Although it is too soon to know when countries around the world will control the COVID-19 pandemic, there is already much to be learned.

To explore trends for 2021, we talked to experts from around the world who specialize in medical research. Here is what we learned.

1. The new normal

Marion Koopman, head of the Erasmus MC Department of Viroscience, predicts that emerging-disease experts will overwhelmingly remain focused on SARS-CoV-2, at least for the coming year.

“I really hope we will not go back to life as we used to know it, because that would mean that the risk of emerging diseases and the need for an ambitious preparedness research agenda would go to the back burner,” Koopman says. “That cannot happen.”

Scientists must stay prepared, because the virus keeps changing. Already, Koopman says, “We have seen spillback [of SARS-CoV-2] into mink in our country, and ongoing circulation with accumulation of mutations in the spike and other parts of the genome.”

Juleen R. Zierath, an expert in the physiological mechanisms of metabolic diseases at the Karolinska Institute and the University of Copenhagen, points out that the pandemic “has raised attention to deleterious health consequences of metabolic diseases, including obesity and type 2 diabetes,” because people with these disorders have been “disproportionally affected by COVID-19.” She notes that the coupling of the immune system to metabolism at large probably deserves more attention.

2. Trial by fire for open repositories

The speed of SARS-CoV-2’s spread transformed how scientists disseminate information. “There is an increased use of open repositories such as bioRxiv and medRxiv, enabling faster dissemination of study and trial results,” says Alan Karthikesalingam, Research Lead at Google Health UK. “When paired with the complementary — though necessarily slower — approach of peer review that safeguards rigor and quality, this can result in faster innovation.”

“I suspect that the way in which we communicate ongoing scientific developments from our laboratories will change going forward,” Zierath says. That is already happening, with many meetings going to virtual formats.

Deborah Johnson, president and CEO of the Keystone Symposia on Molecular and Cellular Biology, notes that while virtual events cannot fully replace the networking opportunities that are created with in-person meetings, “virtual events have democratized access to biomedical research conferences, enabling greater participation from young investigators and those from low-and-middle-income countries.” Even when in-person conferences return, she says, “it will be important to continue to offer virtual components that engage these broader audiences.”

3. Leaps and bounds for immunology

Basic research on the immune system, catapulted to the frontlines of the COVID-19 response, has received a boost in attention this year, and more research in that field could pay off big going forward.

Immunobiologist Akiko Iwasaki at the Yale School of Medicine hopes that the pandemic will drive a transformation in immunology. “It has become quite clear over decades of research that mucosal immunity against respiratory, gastrointestinal, and sexually transmitted infections is much more effective in thwarting off invading pathogens than systemic immunity,” she says. “Yet, the vast majority of vaccine efforts are put into parenteral vaccines.”

“It is time for the immunology field to do a deep dive in understanding fundamental mechanisms of protection at the mucosal surfaces, as well as to developing strategies that allow the immune response to be targeted to the mucosal surfaces,” she explains.

“We are discovering that the roles of immune cells extend far beyond what was previously thought, to play underlying roles in health and disease across all human systems, from cancer to mental health,” says Johnson.

She sees this knowledge leading to more engineered immune cells to treat diseases. “Cancer immunotherapies will likely serve as the proving ground for immune-mediated therapies against many other diseases that we are only starting to see through the lens of the immune system.”

4. Rewind time for neurodegeneration

Oskar Hansson, research team manager of Lund University’s Clinical Memory Research, expects the trend of attempting to intervene against neurodegenerative disease before widespread neurodegeneration, and even before symptom onset, to continue next year.

This approach has already shown potential. “Several promising disease-modifying therapies against Alzheimer’s disease are now planned to be evaluated in this early pre-symptomatic disease phase,” he says, “and I think we will have similar developments in other areas like Parkinson’s disease and [amyotrophic lateral sclerosis].”

Delving deeper into such treatments depends on better understanding of how neurodegeneration develops. As Hansson notes, the continued development of cohort studies from around the world will help scientists “study how different factors — genetics, development, lifestyle, etcetera — affect the initiation and evolution of even the pre-symptomatic stages of the disease, which most probably will result in a much deeper understanding of the disease as well as discovery of new drug targets.”

5. Digital still front and center

“As [artificial intelligence] algorithms around the world begin to be released more commonly in regulated medical device software, I think there will be an increasing trend toward prospective research examining algorithmic robustness, safety, credibility and fairness in real-world medical settings,” says Karthikesalingam. “The opportunity for clinical and machine-learning research to improve patient outcomes in this setting is substantial.”

However, more trials are needed to prove which artificial intelligence works in medicine and which does not. Eric Topol, a cardiologist who combines genomic and digital medicine in his work at Scripps Research, says “there are not many big, annotated sets of data on, for example, scans, and you need big datasets to train new algorithms.” Otherwise, only unsupervised learning algorithms can be used, and “that’s trickier,” he says.

Despite today’s bottlenecks in advancing digital health, Topol remains very optimistic. “Over time, we’ll see tremendous progress across all modalities — imaging data, speech data, and text data — to gather important information through patient tests, research articles or reviewing patient chats,” he says.

He envisions that speech-recognition software could, for instance, capture physician–patient talks and turn them into notes. “Doctors will love this,” he says, “and patients will be able to look a doctor in the eye, which enhances the relationship.”

6. ‘Be better prepared’ — a new medical mantra

One trend that every expert interviewed has emphasized is the need for preparation. As Gabriel Leung, a specialist in public-health medicine at the University of Hong Kong, put it, “We need a readiness — not just in technology platforms but also business cases — to have a sustained pipeline of vaccines and therapies, so that we would not be scrambling for some of the solutions in the middle of a pandemic.”

Building social resilience ahead of a crisis is also important. “[SARS-CoV-2] and the resulting pandemic make up the single most important watershed in healthcare,” Leung explains. “The justice issue around infection risk, access to testing and treatment — thus outcomes — already make up the single gravest health inequity in the last century.”

One change that Peacock hopes for in the near future is the sequencing of pathogens on location, instead of more centrally. “For pathogen sequencing, you need to be able to apply it where the problem under investigation is happening,” she explains. “In the UK, COVID-19 has been the catalyst for us to develop a highly collaborative, distributed network of sequencing capabilities.”

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May, M. 2021: research and medical trends in a post-pandemic world. Nat Med 26 , 1808–1809 (2020). https://doi.org/10.1038/s41591-020-01146-z

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A new gene-editing system tackles complex diseases

Mobes give researchers a new tool in disease modeling.

The human genome consists of around 3 billion base pairs and humans are all 99.6% identical in their genetic makeup. That small 0.4% accounts for any difference between one person and another. Specific combinations of mutations in those base pairs hold important clues about the causes of complex health issues, including heart disease and neurodegenerative diseases like schizophrenia.

Current methods to model or correct mutations in live cells are inefficient, especially when multiplexing -- installing multiple point mutations simultaneously across the genome. Researchers from the University of California San Diego have developed new, efficient genome editing tools called multiplexed orthogonal base editors (MOBEs) to install multiple point mutations at once. Their work, led by Assistant Professor of Chemistry and Biochemistry Alexis Komor's lab, appears in Nature Biotechnology .

Komor's team was especially interested in comparing genomes that differ at a single letter change in the DNA. Those letters -- C (cytosine), T (thymine), G (guanine), A (adenosine) -- are known as bases. Where one person has a C base, another person might have a T base. These are single nucleotide variants (SNVs) or single point mutations, a person might have 4-5 million variants. Some variants are harmless; some are harmful; and often it is a combination of variants that confers disease.

One issue with using the genome in disease modeling is the sheer number of possible variations. If scientists were trying to determine which genetic mutations were responsible for heart disease, they could decode the genomes of a cohort that all had heart disease but the number of variations between any two people makes it very hard to determine which combination of variations causes the disease.

"There is a problem interpreting genetic variants. In fact, most variants that are identified are unclassified clinically, so we don't even know if they're pathogenic or benign," stated Quinn T. Cowan, a recent Ph.D. graduate from the university's Department of Chemistry and Biochemistry and first author on the paper. "Our goal was to make a tool that can be used in disease modeling by installing multiple variants in a controlled laboratory setting where they can be studied further."

An evolution in gene-editing

To understand why MOBEs were created, we have to understand the limitations of the traditional gene-editing tool CRISPR-Cas9. CRISPR-Cas9 uses a guide RNA, which acts like a GPS signal that goes straight to the genomic location you want to edit. Cas9 is the DNA-binding enzyme that cuts both strands of the DNA, making a complete break.

Although relatively straightforward, double-stranded breaks can be toxic to cells. This kind of gene-editing can also lead to indels -- random in sertions and del etions -- where the cell is not able to perfectly repair itself. Editing multiple genes in CRISPR-Cas9 multiples the risks.

Instead of CRISPR, Komor's lab uses a base-editing technique she developed, which makes a chemical change to the DNA, although only one type of edit (C to T or A to G, for example) can be made at a time. So rather than scissors that cut out an entire section at once, base-editing erases and replaces one letter at a time. It is slower, but more efficient and less harmful to cells.

Simultaneously applying two or more base editors (changing a C to T at one location, and an A to G at another location in the genome), allows for better modeling of polygenic diseases -- those occurring due to more than one genetic variant. However, a technology didn't exist that could do this efficiently without guide RNA "crosstalk," which happens when base editors make unwanted changes.

Cowan's MOBEs use RNA structures called aptamers -- small RNA loops that bind to specific proteins -- to recruit base-modifying enzymes to specific genomic locations enabling simultaneous editing of multiple sites with high efficiency and a lower incidence of crosstalk.

This system is novel and is the first time someone used aptamers to recruit ABEs (adenosine base editors) in combination with CBEs (cytosine base editors) in an orthogonal pattern to make the MOBEs.

The differences are stark: when CBE and ABE are given together not using MOBE, crosstalk occurs up to 30% of the time. With MOBE, crosstalk is less than 5%, while achieving 30% conversion efficiency of the desired base changes.

The study was a proof of principle to test the feasibility of the MOBE system, which has been granted a provisional patent. To test them even further, the team conducted several case studies with real diseases, including Kallmann syndrome, a rare hormonal disorder. Their experiments revealed that MOBE systems could be used to efficiently edit relevant cell lines of certain polygenic diseases.

"We're in the process of putting the plasmids up on AddGene so anyone can freely access them. Our hope is that other researchers will use the MOBEs to model genetic diseases, learn how they manifest and then hopefully create effective therapies," stated Cowan.

This research was funded in part by the National Institutes of Health (1R35GM138317, T32 GM008326, and T32 GM112584) and the Research Corporation for Science Advancement (28385).

Full list of authors: Quinn T. Cowan, Sifeng Gu, Wanjun Gu, Brodie L. Ranzau, Tatum S. Simonson, and Alexis C. Komor (all UC San Diego).

• Human Biology
• Diseases and Conditions
• Personalized Medicine
• Chronic Illness
• Heart Disease
• Gene Therapy
• Healthy Aging
• Human genome
• DNA microarray
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• Alzheimer's disease
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Journal Reference :

• Quinn T. Cowan, Sifeng Gu, Wanjun Gu, Brodie L. Ranzau, Tatum S. Simonson, Alexis C. Komor. Development of multiplexed orthogonal base editor (MOBE) systems . Nature Biotechnology , 2024; DOI: 10.1038/s41587-024-02240-0

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Genome Editing: Current Approaches and the Road Ahead in Cancer Research and Therapeutics

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• Konstantina Athanasopoulou 1 ,
• Glykeria N. Daneva 1 ,
• Panagiotis G. Adamopoulos 1 &
• Andreas Scorilas 1  

Part of the book series: Interdisciplinary Cancer Research

Genome engineering has revolutionized the landscape of molecular biology and medical research, offering unprecedented precision in manipulating the genetic material of organisms. Among these, the CRISPR/Cas9 system has emerged as a versatile tool, enabling targeted modifications within the genome. In cancer research, genome editing allows for the targeted disruption of oncogenes and the exploration of genetic factors contributing to tumorigenesis. This knowledge not only enhances our understanding of the fundamental mechanisms underlying diseases but also paves the way for developing personalized therapeutic strategies. Genome editing holds immense promise for tailoring medical treatments to individual genetic profiles. The identification and correction of disease-causing mutations offer unprecedented opportunities to address the root causes of genetic disorders. Moreover, generating genetically modified animal models empowers researchers to investigate diseases within biological systems that are both more pertinent and precise. Genome editing technologies, such as TALENs and ZFNs, represent a paradigm shift in molecular biology, offering unprecedented precision in genetic manipulation. The ongoing advancements in this field have far-reaching implications for both basic research and clinical applications, positioning genome editing as a cornerstone in the journey toward personalized medicine and innovative therapeutic interventions. This chapter provides an overview of the current state of genome editing technologies and their transformative impact on cancer research, with a particular focus on their applications in precision medicine and therapeutic interventions including clinical trials.

Authors Konstantina Athanasopoulou and Glykeria N. Daneva have equally contributed to this chapter.

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Konstantina Athanasopoulou, Glykeria N. Daneva, Panagiotis G. Adamopoulos & Andreas Scorilas

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Athanasopoulou, K., Daneva, G.N., Adamopoulos, P.G., Scorilas, A. (2024). Genome Editing: Current Approaches and the Road Ahead in Cancer Research and Therapeutics. In: Interdisciplinary Cancer Research. Springer, Cham. https://doi.org/10.1007/16833_2024_269

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Synced brains: Why being constantly tuned in to your child's every need isn't always ideal

by Pascal Vrticka, The Conversation

It's crucial for healthy child development that children can form secure attachment bonds with their parents. Decades of research identified one key ingredient for this process: the coordination of parents' and children's brains and behavior during social interactions.

Humans connect with each other by synchronizing in many ways. Called bio-behavioral synchrony, this involves imitation of gestures and the alignment of heartbeats and hormone secretion (like cortisol and oxytocin). Even brains can synchronize —with brain activity decreasing and increasing in the same areas at roughly the same time when we spend time with others.

My colleagues and I carried out research which showed that brain-to-brain synchrony between parent and child can be helpful for children's attachment, and tends to rise when a parent and child play, talk or solve problems together. Recently, however, we started wondering whether more synchrony is always better. Our recent study, published in Developmental Science , suggests it can sometimes be a sign of relationship difficulties.

Is current parenting advice up to date?

A lot of current parenting advice recommends parents to be constantly "in sync" with their kids. It tells parents to be physically close and attuned to their children and to anticipate and immediately respond to their every need.

The advice is building upon attachment theory and research, which show that higher parental sensitivity and reflective functioning are beneficial for child development and secure attachment formation.

Yet, despite its good intentions, this advice misses several important details. For example, research revealed that for about 50-70% of the time , parents and children are not "in sync." During these times, they may be doing separate activities, such as a child exploring something on their own or a parent working. They rather engage in a constant "social dance" comprising being attuned to each other, failing to do so and repairing this disconnect.

And it's this flow of connection, disconnection and reconnection that offers children an ideal mixture of parental support and moderate, useful stress that helps growing children's social brains .

Researchers also agree that there can be negative consequences to parents and children constantly being tuned in to each other. For example, it can increase stress on the relationship and raise the risk for insecure child attachment. That is especially true if it is associated with parents overstimulating their child or being too responsive to their child's every need .

For parent-child synchrony, there thus appears to be an " optimal midrange ." Or, in other words, more synchrony may not necessarily be better.

Brain-to-brain synchrony and attachment

Within a large international team of investigators from across Europe, my colleagues Trinh Nguyen, Melanie Kungl, Stefanie Hoehl, Lars White and I set out to investigate how exactly parent-child bio-behavioral synchrony is linked to attachment.

We invited parent-child pairs—140 parents and their 5-to-6-year-old kids—to our SoNeAt Lab where they solved tangram puzzles together.

We measured brain activity with functional near-infrared spectroscopy (fNIRS) "hyperscanning," for which parents and children were asked to wear caps linked up with optical sensors. We also recorded videos of their interactions so we could assess how much behavioral synchrony they demonstrated—how attuned and attentive they were to each other. And finally, we assessed parents' and children's type of attachment—known as attachment representations .

We previously discovered increased neural synchrony in mother-child and father-child pairs during different tasks. In mother-child pairs, neural synchrony was linked to taking turns in solving puzzles or conversations . And in father-child pairs , synchrony during puzzling was linked to dads being confident about and enjoying their role as fathers. But does that mean higher parent-child neural synchrony is always a measure of a good relationship?

In our new study, we actually observed that mothers who had an insecure, anxious or avoidant attachment type showed more neural synchrony with their children. Interestingly, mothers' attachment types were unrelated to how synced mothers and children were in terms of their behavior. We also found increased neural but decreased behavioral synchrony in father-child pairs (compared to mother-child pairs) independent of attachment.

Our findings suggest that higher neural synchrony may be the result of putting increased cognitive effort into the parent-child interaction. If mothers' attachment representations are insecure, it may be more difficult for mums and kids to coordinate and help each other during activities such as puzzle solving.

A similar explanation may apply to neural synchrony during father-child problem-solving. Dads are more familiar with active, rough-and-tumble play . Engaging in structured and cognitively demanding activities such as puzzles may therefore be more challenging and require more neural synchrony for father-child pairs.

Lessons to be learned

What do our new findings mean? Most importantly, parents should not feel that they must be "in sync" with their kids all the time and at all costs. High parent-child attunement can also reflect interaction difficulties and can often add up to parental burnout , further negatively impacting the parent-child relationship.

It is of course helpful if parents are emotionally available, skilled in reading their children's cues and promptly and sensitively respond to their needs. Especially when children are young. However, it suffices for parents to be " good enough "—to be available when children need them rather than "always on."

Children can also benefit from freedom and independence emotionally, socially and cognitively, especially as they get older.

What really counts is that the parent-child relationship functions well overall. That children can develop trust in their parents and that any mismatches, which naturally occur all the time, are successfully repaired. That's the true essence of attachment theory, which is often missed and misrepresented in parenting advice.

To better navigate the challenging parenting path, parents need access to trustworthy and up to date sources of information. Together with the UK Charity Babygro, we therefore published the free-of-charge Babygro Book for Parents that provides them with evidence-based knowledge on parenting and child development .

It is our hope that our book can empower parents so that they feel reassured and confident in their own parenting choices and can optimally support their children to grow and thrive.

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Physiological Questions, Inventive Approaches

Four vp&s scientists receive schaefer research scholar awards, share this page.

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Four scientists at Columbia University Vagelos College of Physicians and Surgeons have received awards from the Schaefer Research Scholars Program , made possible through a bequest from Dr. Ludwig Schaefer. Each award consists of a $50,000 cash prize and up to $200,000 in direct research support.

Two awardees are full-time VP&S faculty and two are visiting faculty who are collaborating with VP&S faculty:

• Iok In Christine Chio , assistant professor, Institute for Cancer Genetics, Columbia University Vagelos College of Physicians and Surgeons
• Xuebing Wu , assistant professor of medicine, Columbia University Vagelos College of Physicians and Surgeons.
• Stéphane Nedelec , group leader, Institut du Fer à Moulin, Sorbonne Université (host: Hynek Wichterle, Pathology & Cell Biology)
• Ofer Yizhar , associate professor of neurobiology, Weizmann Institute of Science (host: Stavros Lomvardas, Biochemistry & Molecular Biophysics)

Since 2011, the annual Schaefer Scholar Awards have been given to research scientists who have distinguished themselves in the science of human physiology and whose current work is of outstanding merit with significant academic distinction.

Descriptions from the 2024 recipients:

Iok In Christine Chio

Project: “Methionine proteome reactivity in cancer induced cachexia”  

In her Schaefer project, Chio will use unique tools she has created to illuminate the basic mechanisms of cachexia, which could lead to new therapies that transform cancer care.

Cachexia is a severe wasting syndrome that accelerates the loss of muscle throughout the body. Patients weakened by this syndrome often cannot withstand the rigors of cancer therapy and thus experience greater mortality.

Chio’s lab has already uncovered a clue to the origins of cachexia. Loss of fat tissue often precedes muscle loss in cachexia, and some studies suggest that preserving fat can preserve muscle. Chio has found that fat loss in patients with cachexia seems to stem from an increase in an enzyme in fat tissue called MSRA.

Chio’s Schaefer project will test her hypothesis that MSRA promotes cachexia by modulating the methionine oxidation states of specific proteins in fat tissue. These proteins may serve as therapeutic targets or biomarkers of cachexia.

A unique and innovative chemoproteomic platform developed by Chio makes these new studies possible by allowing her to measure the oxidation states of individual methionine residues across the proteome.

Project: “Noncoding translation surveillance in tumor immunogenicity and immunotherapy ”

Wu’s Schaefer study could lead to the development of new cancer vaccines or therapies that improve the effectiveness of immunotherapies.

Immunotherapies are transforming cancer treatment but are ineffective for pancreatic cancer and many other tumors that are adept at hiding from the immune system.

The immune system can easily spot cancers covered with antigens that contain tumor-specific mutations. Tumors with fewer mutations, like pancreatic cancer, can more easily evade detection.

Recent studies have found that tumors can also be covered with “dark” antigens, which do not contain tumor-specific mutations but are generated by aberrant translation of noncoding sequences in cancer cells. Dark antigens, when present in large quantities, can trigger an attack from the immune system. Wu has found clues that cancers that evade the immune system might be suppressing the production of these dark antigens.

Wu will test the hypothesis that pancreatic cancer cells suppress the production of dark antigens by downregulating the BAG6 pathway, a process recently discovered in Wu’s lab, that partially degrades noncoding products and processes them into antigens. If so, he will then determine if increasing BAG6 expression will sensitize tumor cells to immunotherapies.

Stéphane Nedelec

Project: “Human motor neuron diversity and its implications for the etiology of amyotrophic lateral sclerosis”

With support from the Schaefer award, Nedelec will work with Hynek Wichterle’s lab to create improved human in vitro models of amyotrophic lateral sclerosis that should provide new insights into the disorder.

ALS is a late-onset disease that stems from the degeneration of muscle-innervating motor neurons, yet not all motor neurons exhibit the same vulnerability. Little is known about the mechanisms that underlie the differential resistance of adult neurons to ALS, in part due to limitations of existing models of the disease.

The researchers will test the capabilities of a groundbreaking organoid model recently developed in Nedelec’s lab. The 3D cellular system mimics several aspects of human trunk development, including the co-development of spine, spinal cord, muscle cells, and multiple subtypes of motor neurons corresponding to different locomotor circuits.

With the expertise of the Wichterle lab in analyzing motor neurons’ transcriptional programs and studying ALS physiopathology, they will determine if this new type of organoid is a better tool to model the maturation of neuromuscular circuits than current in vitro models of isolated motor neurons. If so, Nedelec will generate organoids from ALS patient-derived and control stem cells to better understand why motor neurons differ in their vulnerability to ALS. Ultimately, his project may open new therapeutic avenues for increasing motor neuron resistance to mutations causing the disease.

Ofer Yizhar

Project: “ A light-driven system for studying neuropeptide signaling using hybrid Opto-GPCRs ”

Oxytocin—a neuropeptide popularly known as the “love hormone”—promotes parenting behaviors and is essential in shaping social behavior throughout an animal’s life.  

Understanding the role of oxytocin in behavior requires molecular tools that can precisely manipulate oxytocin activity within animals, but current methods are either too slow or too broad.

Yizhar’s group recently developed a system that could be used to control circuits activated by the oxytocin receptor and other similar G-protein coupled receptors. The optogenetics system, called OptoGPCRs, deploys rhodopsins that occur naturally in various organisms into mammalian neurons, where they function like inhibitory GPCRs and can be controlled with light.

At Columbia, Yizhar will modify a naturally occurring OptoGPCR to match the profile of brain-resident neuropeptide receptors and validate the system in vitro. Yizhar will then collaborate with the Jones-Marlin, Kahn, and Abdus-Saboor labs at the Zuckerman Institute to assess the ability of this light-driven system to alter behavior, including the reactions of female mice to the sounds of their pups and social huddling among pups. Because the system is highly sensitive to light, OptoGPCRs can be activated non-invasively with overhead light and could become an important tool to study the physiological basis of neuropeptides in early-life social behaviors.

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Justice Department takes 'major step' toward rescheduling marijuana

WASHINGTON — The Justice Department took a significant step toward rescheduling marijuana Thursday, formalizing its process to reclassify the drug as lower-risk and remove it from a category in which it has been treated as more dangerous than fentanyl and meth.

President Joe Biden announced the “major” move in a direct-to-camera video posted to his official account on X. “This is monumental,” Biden said in the message. “It’s an important move towards reversing long-standing inequities. … Far too many lives have been upended because of a failed approach to marijuana, and I’m committed to righting those wrongs. You have my word on it.”

The Biden administration has been signaling that it would move to reschedule the drug from Schedule I — a strict classification including drugs like heroin — to the less-stringent Schedule III, which would for the first time acknowledge the drug’s medical benefits at the federal level. The Drug Enforcement Administration submitted a notice of proposed rulemaking in the Federal Register on Thursday afternoon, triggering a 60-day comment period that will allow members of the public to submit remarks regarding the rescheduling proposal before it is finalized.

Biden first directed federal agencies to review how marijuana is scheduled in October 2022, weeks before that year’s midterm elections. The process was led by the DOJ and the Department of Health and Human Services.

“Look folks, no one should be in jail for merely using or possessing marijuana. Period,” Biden said in Thursday’s video, his third time speaking extensively on the topic since his directive two years ago.

The second time Biden addressed the issue was during this year’s State of the Union address, making history by referring to marijuana from the dais in the House chamber. “No one should be jailed for using or possessing marijuana,” he said at the time.

Vice President Kamala Harris also released a video Thursday, hailing the progress.

“Currently marijuana is classified on the same level as heroin and more dangerous than fentanyl. We are finally changing that,” Harris said. “We are on the road to getting it done.”

During the first 30 days of the comment period, interested parties could request a hearing regarding the rescheduling proposal. Under the statute, the DEA would be required to hold a hearing before an administrative law judge.

After the DEA reviews and considers the public comments, and at the conclusion of any requested hearing, the DEA will issue a final order to reschedule marijuana. (The DEA could decline to reschedule the drug but that’s unlikely given the administration’s strong support).

The entire process can take anywhere from a few months to up to a year.

Once completed, federal scientists will be able to research and study the potential medical benefits of the drug for the first time since the Controlled Substances Act was enacted in 1971. It could also open the door for pharmaceutical companies to get involved with the sale and distribution of medical marijuana in states where it is legal.

For the $34 billion cannabis industry, the move would also eliminate significant tax burdens for businesses in states where the drug is legal, notably removing it from the IRS code’s Section 280E, which prohibits legal cannabis companies from deducting what would otherwise be ordinary business expenses.

The Justice Department’s rescheduling decision could also help shrink the black market, which has thrived despite legalization in states like New York and California, and has undercut legal markets, which are fiercely regulated and highly taxed.

Dr. Kevin Sabet, president of the anti-marijuana legalization group Smart Approaches to Marijuana, blasted the decision. “It’s become undeniable that politics, not science, is driving this decision and has been since the very beginning. This decision won’t legalize marijuana, and it won’t release anyone from prison or jail,” Sabet said. “This is setting the stage to create the Big Tobacco of our time.”

During his time in office, Biden issued pardons for prior federal offenses of simple possession of marijuana and issued a proclamation granting additional pardons for simple possession, attempted simple possession and use of the drug.

The White House has also urged governors to do the same in their states and some have heeded the call, including in Oregon and Massachusetts.

Democrats in Congress are pursuing a partisan effort to remove cannabis entirely from the Controlled Substances Act, empowering states to create their own cannabis laws and prioritize restorative and economic justice for those affected by the “war on drugs.”

“Congress must do everything we can to end the federal prohibition on cannabis and address long-standing harms caused by the War on Drugs,” Senate Majority Leader Chuck Schumer, D-N.Y., said earlier this month.

Julie Tsirkin is a correspondent covering Capitol Hill.

Monica Alba is a White House correspondent for NBC News.