A dynamic picture of how we respond to high or low oxygen levels
A new study from Gladstone Institutes sheds light on the molecular workings at play when oxygen exceeds normal levels, with findings that may one day inform the decision to use supplemental oxygen as a medical treatment.
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GLADSTONE ASSISTANT INVESTIGATOR Isha Jain, PhD, SENIOR AUTHOR OF THE NEW STUDY, DISCUSSES THE RESEARCH WITH FIRST AUTHOR KIRSTEN XUEWEN CHEN. THEIR FINDINGS EXPLAIN HOW BREATHING AIR WITH DIFFERENT LEVELS OF OXYGEN AFFECTS THE CREATION AND DEGRADATION OF DIFFERENT PROTEINS IN THE LUNGS, HEART, AND BRAIN OF MICE.
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SAN FRANCISCO—December 8, 2023—It only takes holding your breath for slightly too long to understand that too little oxygen is bad for you. But can you also have too much? Indeed, breathing air with a higher oxygen level than your body needs can cause health problems or even death.
But with scant research on the topic, scientists have known little about how the body senses too much oxygen. Now, a new study from Gladstone Institutes has greatly expanded the scientific body of knowledge about the mechanisms at play, and why it matters for health.
Their findings, reported in the journal Science Advances, explain how breathing air with different levels of oxygen—from too little, to just right, or too much—affects the creation and degradation of different proteins in the lungs, heart, and brain of mice. Notably, the study also highlights a particular protein that may play a central role in regulating how cells respond to hyperoxia.
“These results have implications for many different diseases,” says Gladstone Assistant Investigator Isha Jain, PhD, senior author of the new study. “More than 1 million people in the US breathe supplemental oxygen every day for medical reasons, and studies suggest it could be making things worse in some cases. That’s just one setting where our work is starting to explain what’s happening and how the body responds.”
Understanding Oxygen’s Effects
Most prior research on oxygen levels has examined the molecular effects of too little oxygen. And even in that realm, most of the focus has been on how low oxygen affects which genes are turned on or off.
“Our study enters uncharted territory by using mice and looking downstream of gene expression at which proteins abnormally accumulate or degrade in response to different oxygen concentrations,” says Kirsten Xuewen Chen, first author of the new paper and a graduate student at UC San Francisco.
The research builds on the team’s prior work, which revealed that in response to too much oxygen, certain proteins containing iron and sulfur clusters become degraded, leading cells to malfunction.
“Now, we wanted to get a more dynamic picture of how proteins are regulated when oxygen levels are too high or too low,” Chen says.
To do so, the team exposed mice for several weeks to air with oxygen level of 8 percent, 21 percent (the usual level we breathe in Earth’s atmosphere), or 60 percent. Meanwhile, they gave the mice food containing a distinct form of nitrogen that the animals’ bodies incorporated into new proteins. This nitrogen isotope acted as a “label” that enabled the researchers to calculate protein turnover rates—the balance between protein synthesis and degradation—for thousands of different proteins in the lungs, heart, and brain.
“We’re grateful to our collaborators who are the experts in this technique, known as stable isotope labeling of amino acids in mice,” Jain says. “Without it, we could not have done this study.”
A Key Protein Builds Up
The researchers found that oxygen levels more dramatically affected proteins in the lungs of mice than the heart or brain. They identified certain proteins with abnormal turnover rates under high- or low-oxygen conditions.
One particular protein that accumulated in high-oxygen conditions, MYBBP1A, piqued their attention. MYBBP1A is a transcription regulator, meaning it directly affects gene expression.
“This caught our eye because prior research has shown that other transcription factors called hypoxia-inducible factors, or HIFs, play a big role in cells’ response to low oxygen,” Chen says. “Our work nominates MYBBP1A for a related role in hyperoxia signaling.”
MYBBP1A is involved in the production of ribosomes—cellular “machines” that build proteins. Further experiments surfaced clues that, in response to high oxygen levels, accumulation of this protein in the lungs may affect production of ribosomal RNA, a key component of ribosomes.
Jain’s team is now examining the precise molecular role of MYBBP1A during hyperoxia, including whether its response is protective or harmful. This work could set the stage for novel treatments that target the MYBBP1A protein or associated molecules in ways that counter the bad effects of hyperoxia—similar to widespread research efforts targeting HIF proteins in low-oxygen conditions.
First-of-Its-Kind Dataset
The new study presents a first-of-its kind dataset of protein turnover rates in different tissues of mice exposed to different oxygen levels. The team hopes its results will inspire other researchers to further investigate the effects of too much or too little oxygen on the body, which could transform the way we treat disease.
About the Study
The paper “In Vivo Protein Turnover Rates in Varying Oxygen Tensions Nominate MYBBP1A as a Novel Mediator of the Hyperoxia Response” was published in the journal Science Advances on December 8, 2023.
In addition to Jain and Chen, other authors of the study are: Augustinus Haribowo, Alan Baik, Andrea Fossati, Erica Stevenson, Michela Traglia, Alexander Pico, and Danielle Swaney of Gladstone; Yiwen Chen and Daniel Jarosz of Stanford University; Nabora Reyes, Tien Peng, Michael Matthay, and Abigail Buchwalter of UC San Francisco; and Sina Ghaemmaghami of the University of Rochester
This work was supported by the American Heart Association, the California Institute for Regenerative Medicine, the National Institutes of Health (T32-HL007731, NIH DP5 DP5OD026398), the Chan Zuckerberg Biohub, the Sarnoff Cardiovascular Research Foundation, the UCSF Program for Breakthrough Biomedical Research, the Tobacco-Related Disease Research Program, and a gift from Dave Wentz.
About Gladstone Institutes
Gladstone Institutes is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. Established in 1979, it is located in the epicenter of biomedical and technological innovation, in the Mission Bay neighborhood of San Francisco. Gladstone has created a research model that disrupts how science is done, funds big ideas, and attracts the brightest minds.
JOURNAL
Science Advances
ARTICLE TITLE
In Vivo Protein Turnover Rates in Varying Oxygen Tensions Nominate MYBBP1A as a Mediator of the Hyperoxia Response
ARTICLE PUBLICATION DATE
8-Dec-2023
Reducing oxygen levels for children in intensive care will save lives
Reducing oxygen levels in critically ill children on mechanical ventilators in intensive care could save tens of young lives each year, finds a new study led by researchers at UCL and Great Ormond Street Hospital.
The study, funded by the National Institute for Health and Care Research and published in The Lancet, also found that lower levels of oxygen would reduce the number of days children spent on machines supporting organs, saving the NHS £20million every year.
Lead author, Professor Mark Peters (UCL Great Ormond Street Institute of Child Health and Consultant Paediatric Intensivist at GOSH), said: “Giving the minimum safe dose of anything in intensive care appears to generate the best outcomes, so we wanted to test this approach with oxygen. We found a small benefit of lower oxygen targets that is unlikely to have been due to chance. But because so many children are treated with oxygen, this has the potential to improve outcomes and reduce healthcare costs in the UK and around the world.
“This could have particular implications in countries where oxygen is a scare resource, or in situations as we have seen in recent years, where health needs change, and oxygen demand quickly peaks.”
In the UK, around 20,000 children are admitted to intensive care each year and roughly 75% will receive additional oxygen through a ventilator.
Oxygen is one of the most common treatments used in emergency situations. Doctors and nurses adjust oxygen treatment based on how much oxygen their patient has in their blood. While very low oxygen levels are harmful, current research shows that slightly lower than normal levels may be the best target for very ill people.
The Oxy-PICU study is the largest randomised controlled trial ever conducted in paediatric intensive care units (PICUs). It was led by researchers from UCL and Great Ormond Street Hospital (GOSH), the Intensive Care National Audit & Research Centre (ICNARC) and the Paediatric Critical Care Society Study Group (PCCS-SG).
The researchers recruited 2,040 children from 15 NHS PICUs across England and Scotland. Each of the children required a mechanical ventilator and extra oxygen on admission to the PICU.
The children, who ranged from newborn up to 16 years, were randomly allocated to one of two groups, either receiving oxygen to the standard target level (saturation “SpO2” > 94%), or a reduced oxygen target (SpO2 88-92%). The percentages refer to the proportion of the oxygen-carrying capacity of the blood that is being used.
The researchers found that the children who received the lower level of oxygen were 6% more likely to have a better outcome, either in terms of survival or the number of days spent on machines supporting their organs.
The researchers anticipate that if the approach was scaled up across the NHS, it could save 50 lives, 6,000 ICU bed days and £20million annually in the UK alone.
The Oxy-PICU study is funded by the NIHR’s Health Technology Assessment programme and supported by the NIHR’s Biomedical Research Centres at GOSH and UCLH.
Lauran O’Neill, Senior Critical Care Nurse at GOSH, said: “This is a major milestone study, which was nurse-led, with research taking place at the bedside as part of normal clinical care. It’s a great example of a research-hospital vision as every child admitted to ICU was screened for inclusion into the study.”
Professor Marian Knight, Scientific Director for NIHR Infrastructure, said: “The main purpose of all NIHR health and care research is to save or improve lives in some way, whether by questioning what we currently do or introducing new practice.
“This landmark nurse-led study has challenged the accepted practice for providing oxygen to children in intensive care in a way that could have a global impact. We are proud to have supported Professor Peters and his team through both our Health Technology Assessment programme, our Biomedical Research Centre at GOSH, and with our remarkable NIHR research nursing staff.”
Dilly and Noah’s story
When two-year-old Noah Karunananthan was diagnosed with leukaemia in May 2022 after a trip to A&E at Hillingdon Hospital, his family were devastated. Noah lives with his mum Dilly, dad Sabe and twin sister Naima in Hillingdon, West London. In order to give him the medication he urgently needed, the doctors had to sedate him, and he was quickly transported for treatment at Great Ormond Street Hospital (GOSH).
Mum Dilly says: “We were told Noah had blood cancer but we didn’t know what kind it was - it was really overwhelming. But the team came in and looked after him, they told us everything they were going to do, every step of the way and he had 1 to 1 care which I thought was amazing.”
Noah was in the ICU for around 4 days to support his organs while he received care. While there, his parents consented to him taking part in the Oxy-PICU trial as part of his recovery journey. He was later transferred to the oncology ward.
Dilly said: “I was so stunned when we got to the ICU, it was like a spaceship. I was in awe of all the machines, in shock really, and exhausted as it was the middle of the night.
“He was started on the Oxy-PICU trial before the team took us there in the ambulance. He had the new treatment of lower oxygen saturation targets.
“Noah had a brain biopsy to extract a suspected fungal infection – this scared the hell out of us. What was amazing was how he recovered. For three months he’d had almost no facial expressions – we hadn’t seen him smile. But then his daily Occupational Therapist Mary came one day and you could see him try to smile at her toys. After that session we could see him slowly getting better.
“This September, we signed up to nursery and we were worried Noah may not be able to do a full day but he’s thriving there! This is the first time we have been separated for longer periods and I can see that he loves learning and exploring.
“If Noah, or we as a family, can help children, parents and families through research we are happy to. He was one of the first people to try many of the research projects we have signed up to and it makes us proud that Noah has been able to help give some answers that may have helped him and could now help someone else and it’s all part of our journey.”
JOURNAL
The Lancet
ARTICLE TITLE
Conservative versus liberal oxygenation targets in critically ill children (Oxy-PICU): a multiple centre, open, parallel group, randomised clinical trial
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