But despite their promise, cell-based therapies still face important limitations, including toxicity and the possibility that they could attack healthy cells. In addition, scientists don’t have a good handle on how to modify existing therapeutic cells to expand their applications or better control their activity.

To overcome these limitations, researchers at Gladstone Institutes and UC San Francisco (UCSF) undertook a systematic analysis of the molecular building blocks used to engineer therapeutic cells. Their work, reported in the journal Cell, resulted in a comprehensive rule book for the design of therapeutic cells with improved specificity and safety, and for the eventual customization of cell-based therapies.

“We have identified principles that should greatly facilitate the engineering of therapeutic cells with greater sensitivity, accuracy, and safety than was possible before,” says Kole Roybal, PhD, an associate professor in the Department of Microbiology and Immunology at UCSF, an affiliate investigator at Gladstone Institutes and core member of the Gladstone-UCSF Institute of Genomic Immunology, a Parker Institute for Cancer Immunotherapy investigator, and the study’s senior author. “Our work will provide biomedical researchers with a toolkit for directing a range of cell-based therapies to their intended targets and for programming their therapeutic activities.”

Building a Better Receptor

At the core of most therapeutic cells is a molecule called a receptor. Receptors are large proteins that straddle the cell’s outer membrane. Their outer portion recognizes a specific target (for instance a protein on the surface of a cancer cell) and their inner portion tells the cell what to do upon recognizing this target. One way to engineer a therapeutic cell is to insert in a cell — often an immune cell called a T cell — a synthetic receptor made by piecing together fragments of known receptors.

This approach was used to create CAR-T cells, which have proven very effective at eliminating some types of blood cancers. CAR-T cells harbor a “chimeric antigen receptor” (CAR) that is based on a receptor normally found in T cells.

Starting with a different backbone, Roybal previously developed a receptor called synNotch that can direct T cells to better recognize and kill solid tumors. Since this early stage research, Roybal’s lab has shown how synNotch can be used in combination with CARs to develop next-generation cell therapies for ovarian cancer and mesothelioma. The synNotch receptor allows scientists to precisely control when and where the therapeutic T cell is active.

“These smart cell therapies can unleash potent therapeutic activity precisely at the site of disease, improving the efficacy of the therapy and reducing the chance of life-threatening toxicities seen in patients,” says Roybal.

However, the original synNotch receptor is difficult to deploy for cell-based therapy in humans. For one thing it is bulky, which makes it difficult to insert into human cells. For another, some of its parts come from mouse, yeast, and viruses instead of human receptors, which could lead to immune rejection of the engineered cells once introduced in a patient.

To understand what they could keep and remove from the synNotch receptor without losing its desirable features, the Roybal team systematically swapped out various portions of the receptor. After inserting the modified receptors in human T cells, the scientists tested their ability to recognize their intended targets and activate the expected response.

“A challenging but fun feat was figuring out how different parts of known receptors function, so that we could take those pieces apart and put them back together in novel ways to meet our design specifications,” says Raymond Liu, PhD, a first author of the study and postdoctoral fellow in Roybal’s lab.

In the end, the team produced a catalog of receptors they dubbed SNIPRs, which are small enough for cost-effective engineering into human cells. They are also made exclusively from human receptor fragments and can detect and respond to even small amounts of their targets. In addition, the activity of SNIPRs can be adapted so that cells that harbor them don’t just kill target cells, but can also deliver specific molecules to precise disease locations.

“Understanding the rules of receptor design allowed us to build receptors that are more effective and also better suited for clinical translation,” says Iowis Zhu, a graduate student in the Roybal Lab and the other first author of the new study.

A Platform for Next-Generation Cell Therapy

The researchers next assessed the ability of these optimized receptors to clear tumors in mouse models of leukemia, mesothelioma, and ovarian cancer.

To reduce the chances of killing non-target cells, they combined a SNIPR designed to recognize one molecule on the tumor with a CAR receptor tuned to another tumor molecule. Moreover, they made the production of the CAR receptor dependent on the activation of the SNIPR receptor. This way, only cells carrying the targets of both the synNotch and the CAR receptors would be killed, while cells carrying only one target would not.

In each of the three cancer types they tested, this two-step targeting strategy led to more selective elimination of cancer cells than could be achieved with either receptor alone, highlighting the promise of this approach to reduce off-target toxicity of cell therapies.

Cell therapies based on SNIPRs are now being optimized for the treatment of ovarian cancer, renal cancer, prostate cancer, and glioblastoma in both the academic setting and a company called Arsenal Bio, co-founded by Roybal.

And cancer may not be the only condition that could be treated with SNIPR-based cell therapy.

This receptor system is also amenable to enhancing the anti-inflammatory activity of immune cells for the treatment of autoimmunity. In addition, SNIPRs could be used to target stem cells or other cell types to detect tissue damage and induce tissue repair or the reversal of fibrosis.

“Engineered cells have the potential to operate as much smarter therapeutics than traditional small molecules and biologics,” says Roybal. “We’re hoping our new receptor system will serve as a technology platform enabling scientists and clinicians to design safer, targeted, and more effective cell-based therapies against cancer and many other diseases.”

The treatment that has been tested is carbonic anhydrase (CA) inhibition, CA being an enzyme that serves to maintain a balance between carbonic acid and carbon dioxide in the body. Several drugs with CA inhibitory properties are already available on the market, and used for treatment of glaucoma, epilepsy and other disorders.

Previous research has not systematically tested whether CA inhibitors also might be used to treat obstructive sleep apnea. The current study was a randomized double-blind clinical trial, and 59 patients with moderate or severe sleep apnea completed it. Patients were randomly assigned to two groups receiving either 400 or 200 mg of the CA inhibitor, and a third group (the control group) that received placebo. The study lasted for four weeks.

Fewer breathing pauses

The results show that, overall, the treatment reduced the number of breathing pauses and promoted oxygenation during the night. A few patients experienced side effects, such as headache and breathlessness, which were more common in those receiving the highest dose.

The study results together with established safety data of the drug sulthiame provide support for continued research on CA inhibition as a new potential treatment for obstructive sleep apnea.

“Among the patients who received the higher dosage of the drug, the number of breathing pauses decreased by approximately 20 per hour. For just over a third of patients in the study, only half of their breathing pauses were left, and in one in five the number fell by at least 60 percent,” says Jan Hedner, Professor of Pulmonary Medicine.

The fact that several approved drugs in the CA inhibitor category are available on the market makes fast-tracking development of an approved drug for sleep apnea practicable. The drug used in this clinical trial was sulthiame, which is sometimes used to treat epilepsy in children.

Treatment options needed

Today, treatment for a patient with sleep apnea is either an oral appliance therapy or a CPAP (Continuous Positive Airway Pressure) mask. Both help to maintain airway patency during sleep.

“These therapy options take time to get used to and, since they frequently are perceived as intrusive or bulky. Insufficient user time is therefore common. If we develop an effective drug, it will therefore make life easier for many patients and, in the long run, potentially also save more lives,” says Ludger Grote, Senior Lecturer at Sahlgrenska Academy, University of Gothenburg.

The German pharmaceutical company Desitin Arzneimittel GmbH funded the trial, and the results are published in the American Journal of Respiratory and Critical Care Medicine.

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Liquid droplets and very fine particles can trap light — similar to how light can be caught between two mirrors. As a result, the intensity of the light inside them is amplified. This also happens in very fine water droplets and solid particles in our atmosphere, i.e. aerosols. Using modern X-ray microscopy, chemists at ETH Zurich and the Paul Scherrer Institute (PSI) have now investigated how light amplification affects photochemical processes that take place in the aerosols. They were able to demonstrate that light amplification causes these chemical processes to be two to three times faster on average than they would be without this effect.

Using the Swiss Light Source at the PSI, the researchers studied aerosols consisting of tiny particles of iron(III) citrate. Exposure to light reduces this compound to iron(II) citrate. X-ray microscopy makes it possible to distinguish areas within the aerosol particles composed of iron(III) citrate from those made up of iron(II) citrate down to a precision of 25 nanometres. In this way, the scientists were able to observe and map in high resolution the temporal sequence of this photochemical reaction in individual aerosol particles.

Decay upon exposure to light

“For us, iron(III) citrate was a representative compound that was easy to study with our method,” says Pablo Corral Arroyo, a postdoc in the group headed by ETH Professor Ruth Signorell and a lead author of the study. Iron(III) citrate stands in for a whole range of other chemical compounds that can occur in the aerosols of the atmosphere. Many organic and inorganic compounds are light-sensitive, and when exposed to light, they can break down into smaller molecules, which can be gaseous and therefore escape. “The aerosol particles lose mass in this way, changing their properties,” Signorell explains. Among other things, they scatter sunlight differently, which affects weather and climate phenomena. In addition, their characteristics as condensation nuclei in cloud formation change.

As such, the results also have an effect on climate research. “Current computer models of global atmospheric chemistry don’t yet take this light amplification effect into account,” ETH Professor Signorell says. The researchers suggest incorporating the effect into these models in future.

Non-uniform reaction times in the particles

Now precisely mapped and quantified, the light amplification in the particles comes about through resonance effects. The light intensity is greatest on the side of the particle opposite the one the light is shining on. “In this hotspot, photochemical reactions are up to ten times faster than they would be without the resonance effect,” says Corral Arroyo. Averaged over the entire particle, this gives an acceleration by the above-mentioned factor of two to three. Photochemical reactions in the atmosphere usually last several hours or even days.

Using the data from their experiment, the researchers were able to create a computer model to estimate the effect on a range of other photochemical reactions of typical aerosols in the atmosphere. It turned out that the effect does not pertain just to iron(III) citrate particles, but all aerosols — particles or droplets — made of compounds that can react with light. And these reactions are also two to three times faster on average.

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Materials provided by ETH Zurich. Original written by Fabio Bergamin. Note: Content may be edited for style and length.

The study, published in the Journal of Occupational Health Psychology recently, also found that working on a day when you feel ill drains mental energy which cannot be recovered the next day.

The study seeks to shed further light on the phenomenon of ‘presenteeism’ — defined by the researchers as continuing to work when experiencing ill-health. The practice has been labelled an ‘800-pound gorilla’ by researchers in occupational health psychology because of the tremendous costs it inflicts on employees and organisations alike. These costs include burnout, impaired workability, and productivity loss.

This study led by Dr Wladislaw Rivkin, Associate Professor in Organisational Behaviour, Trinity, deepens our understanding of the harmful impact of presenteeism on employee effectiveness by demonstrating that depletion of mental resources is a key mechanism responsible for these harmful effects.

The research involved 126 employees logging their daily productivity across 12 workdays, resulting in 995 daily work observations. It was conducted during the COVID-19 lockdown in 2020 when all participants were working from home.

Dr Rivkin commented:

“It is crucial to tackle daily presenteeism, especially for remote workers. Managers should openly discourage presenteeism by reassuring team members that if they feel unwell it is acceptable to reduce their daily work goals and instead tend to their health. In light of the energy-depleting nature of presenteeism if employees engage in presenteeism they should work on tasks that are inherently pleasant rather than tedious tasks that further drain their energy.

“So, while it may seem a good idea to work despite ill health to deliver on work goals our research shows that this has a knock-on effect for remote workers’ performance on the next day as presenteeism drains employees’ psychological energy, which cannot be fully recovered after work.”

The full paper was entitled “Should I stay or should I go? The role of daily presenteeism as an adaptive response to perform at work despite somatic complaints for employee effectiveness.”

Wlad Rivkin is an Associate Professor in Organisational Behaviour and Work Psychology whose research focuses on burnout, stress and other demands that people experience at work as well as what organisations can do to protect employee wellbeing and maintain their effectiveness. Other recent research projects include studies on the impact of commuting on employee wellbeing, the role of willpower in overcoming the negative effects of a bad night’s sleep and how smartphone use during non-work time impacts on sleep quality.

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