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100 times more "love hormone" than previously thought

Siri Leknes, Ole Kristian Brandtzæg og Steven Ray Wilson
Oxytocin researchers: PhD student Ole Kristian Brandtzæg (center) did such a good job that he deserves oxytocin-inducing cuddling and a hug, according to Siri Leknes and Steven Ray Wilson. Photo: Bjarne Røsjø. Bruk bildet.

100 times more "love hormone" than previously thought

Scientists at the University of Oslo have shown that the content of the "love hormone" oxytocin in blood plasma and serum is about 100 times higher than previously thought. At the same time, they documented the benefits of Open Science and new publishing methods: Better science, faster publication, larger outreach.

Oxytocin – also known as the "love hormone" or the "cuddle hormone" – has a number of important functions in the body of humans and other mammals. The hormone is produced in the hypothalamus in the brain, for example in women giving birth – when it helps in creating an emotional connection between mother and child. Hospitals use oxytocin to induce labour or start lactation when necessary.

Oksytocin er både en nevrotransmitter og et hormon
Structure: Oxytocin is a peptide consisting of nine linked amino acids. Illustration: Colourbox.

In the wake of spectacular findings in e.g. rats (where mothers sometimes eat their own children if they lack oxytocin), the study of oxytocin in humans has become "hot". 

The drug is believed to increase empathy and attention towards social cues from others. A study at the University of Oslo in 2012 showed that nasal spray containing oxytocin improves our ability to interpret other people’s facial expressions.

“However, we don’t know if oxytocin is necessary for emotional connections between people, because it is not possible to block oxytocin in humans. Therefore, it is very important to have precise methods for measuring the amounts of the substance in different individuals”, says Associate Professor Siri Leknes at the University of Oslo’s Department of Psychology.

“But it has been a big problem that we didn’t have a method for measuring the levels of oxytocin in a precise manner", explains Associate Professor Steven Ray Wilson at the Department of Chemistry.

Therefore, there have been many hot discussions among scientists in recent years. Several reports on the links between oxytocin and human emotions have in fact been unreliable, Wilson adds. On the other hand, reports about the link between oxytocin and behaviour seem to have been more reliable.

Precise measurements of oxsytocin

But now, the problem of measuring oxytocin is probably solved. A multidisciplinary research group with members from the Department of Chemistry and the Department of Psychology at the University of Oslo (UiO) has developed and documented a new measuring method, which is already being recognized as more precise than all older methods.

The new method has already been used to prove that the real content of oxytocin in blood plasma and serum in humans is approximately 100 times higher than previous methods suggested. The scientific paper that presents this discovery was published in Nature’s Open Access journal Scientific Reports August 16 2016 and has attracted much attention.

“Oxytocin is a peptide – that is a short protein – with a very special, double function. It acts as a neurotransmitter in the brain, which means that it transmits signals between nerve cells. Oxytocin in the brain is believed to cause such things as increased empathy. But when oxytocin is in the blood, it acts as a hormone that regulates bodily processes”, Leknes explains.

“But without precise methods for measuring, it has been difficult to know if there is a clear correlation between oxytocin levels in the blood and the brain. For example, oxytocin nasal spray or injections introduces the drug into the bloodstream, but how much of the substance is able to pass through the blood-brain barrier and affect the brain? We believe that our measurement method will help to provide new and more accurate answers about this”, Wilson adds.

Oxytocin was almost invisible

The project was initiated by neuroscientist Siri Leknes, who has published many scientific articles on oxytocin but didn’t like that different methods gave different answers to how much oxytocin is contained in human blood. She contacted chemist Steven Ray Wilson, who specializes in measuring substances in the body.

“We joined forces in order to develop a method that could provide accurate measurements of oxytocin, but this was more difficult than you might think. After much work, we found that oxytocin in the blood binds very strongly to several proteins, while only a small percentage is dissolved in blood plasma and serum. This means that most of the oxytocin molecules have been invisible to many measurement techniques”, says  Wilson.

Professor Elsa Lundanes og stipendiaten Ole Kristian Brandtzæg foretar massespektrometri-analyser i laboratoriet for bioanalytisk kjemi ved Kjemisk institutt.
Professor Elsa Lundanes and PhD student Ole Kristian Brandtzæg participated in the study, using mass spectrometry to determine the real content of oxytocin in the blood. Photo: Bjarne Røsjø.  Download the picture.

Breaking the bond

The breakthrough came when PhD student Ole Kristian Brandtzæg at the Department of Chemistry, who is first author on the article in Scientific Reports, found a technique that could break the bond between proteins and oxytocin.

“Proteins consist of long molecular chains that are folded together in a special three-dimensional structure. Our technique is to "stretch out" the proteins, and this causes them to release the oxytocin, Brandtzæg explains.

"Thus, the total amount in the blood becomes available for analysis, and the amount of “love hormone” can be determined by using mass spectrometry. This technique makes it possible to determine exactly which substances, and the quantities of them, that exist in biological samples", Brandtzæg adds.

“When we saw that the total amount of oxytocin in the blood is about 100 times higher than previously thought, it was like getting a small shock. This suggests that many previous findings should be reassessed”, implies Wilson.

The scientists are now wondering about the effects oxytocin might have when it is bound to proteins. Maybe the oxytocin causes the proteins to change their function? Or, could the protein/oxytocin complexes act as a reservoir that can quickly release oxytocin when needed? And: how is the relationship between the amount of oxytocin bound to proteins, and the amount dissolved in the blood? Does an increased amount in blood lead to a proportional increase in protein/oxytocin complexes?

“We don't know yet, but we sought advice from Knut Fredrik Seip at the University’s School of Pharmacy. We came to the conclusion that the best thing we could do was to measure the total amount of oxytocin. Not only the dissolved part”, says Wilson.

Open Science: Better, faster, more outreach

“It has been very interesting to work interdisciplinary in this project, which we believe is right in the middle of the life science “zeitgeist” now sweeping across the UiO. But we have also learned another important lesson, because we experienced the advantages of Open Access and Open Science”, says Wilson.

This learning happened because the scientists at UiO chose an original approach when publishing their results. This led to a broader international collaboration, faster publication, and greater outreach.

The usual process until now has been that scientists who want to publish their results submit their paper to a renowned scientific journal. The first response of the editors is to send the article to a small handful of independent scientists for assessment (peer review). This approval process can take months or maybe more than a year, and the delay can be frustrating for impatient scientists with a new story to tell.

The peer review process often leads to a rewrite of the paper, but in the end, the final paper is published – and hidden behind a high paywall. Researchers are publicly funded, the peer reviewers work without a fee, but the magazines are owned by large private publishing companies like Elsevier and Springer and generate enormous profits.

ADDITIONAL READING: The chemistry that provides better health Care: Personalized medicine is the new mantra of the Health Care system. Chemists at UiO are contributing in the development of simpler, faster and more reliable tools of diagnostics.

The alternative to this state of affairs is Open Access – free access to research results - and Open Science, which is a broader concept in which also raw data, methods, software, etc. can be made public..

Preprint: «Tinder for scientists»

The UiO scientists chose to publish an early version of their paper on a so-called preprint server. Such servers are established with the purpose of giving scientists the possibility of receiving feedback from other scientists before papers are submitted to peer review.

“In this case, the preprint caught the attention of a research group at Duke University in the United States. They read the preprint and tested the method, and came back to us with a confirmation that the method had worked also for them. This was a new experience for us”, Wilson relates.

The American scientists also sent their results to their Norwegian colleagues, who promptly included them as co-authors of the final paper that was submitted to Scientific Reports. This caused the peer review process to become more or less a formality, because the new method had already been critically evaluated, tested and verified by independent scientist. This is of great value, because singular scientific experiments and results should preferably be reproduced and tested before being generally accepted as “new knowledge”.

“My conclusion is that preprint servers, in this case biorxiv.org, can function as "Tinder for scientists," comments Wilson. He is referring to the matchmaking website where single people can meet like-minded others in order to start new amorous relationships.

The UiO scientists developed the method for analyzing human blood, but the scientists at Duke tested the new method while investigating the relationship between oxytocin and the temperament of dogs. They were for instance investigating whether oxytocin can make dogs less aggressive. The results of this survey will probably soon published.

Preprint publishing is relatively widespread among physicists, but is not a common practice among biologists, neuroscientists and chemist. Steven Wilson’s impression is that many scientists don’t even know that most scientific journals, including Science and Nature, accept the principle.

Spreading like wildfire

Wilson, who is an ardent supporter of Open Access, notes that preprint publishing and data sharing provide a number of advantages.

Ole Kristian Brandtzæg, Siri Leknes og Steven Ray Wilson
Ole Kristian Brandtzæg, Siri Leknes and Steven Ray Wilson found that preprint publishing was a sort of «Tinder for scientists". Photo: Bjarne Røsjø.  Download the picture.

“Some scientists fear that other scientists can "steal" your results if you publish them as a preprint, but we experienced the opposite. In principle, preprinting is safe because everything is recorded in a database which proves that "I got there first," and this prevents other scientists from stealing data and results. The procedure also reduces the risk that other researchers will have the same idea and perhaps publish a paper while your own manuscript is still being peer reviewed. In this case, we also could include several new scientists and more data into the final paper”, comments Wilson.

The scientists also experienced another benefit of Open Science, after the publication August 16th: The paper spread almost like wildfire on social media.

“One week after publishing, the paper had been tweeted and retweeted to such a degree that it was in the top five percent of shared papers from Scientific Reports. The paper thus was spread both faster and wider than traditional publishing behind a paywall probably would have led to”, says Wilson.

Steven Wilson and Ole Kristian Brandtzæg are members of the research group Diatech@UiO, which was established to break barriers in medical diagnostics. The Diatech-affiliated scientists are among the best in the world when it comes to analyzing blood samples and other biological samples. Brandtzæg’s PhD scholarship was funded through the multifaculty priority research area  Molecular Life Science (MLS) at the UiO.

“The prior methods for analyzing oxytocin have mostly gone via antibodies, but this creates uncertainty because antibodies can bind to a lot of other substances. My impression is that the recent trend moves towards increased use of mass spectrometry, which we used in this project, both in hospitals and among scientists. Mass spectrometry is, incidentally, widely used to expose athletes who use doping”, says Wilson.

Read more on Titan.uio.no:

The Chemistry that provides better Health Care

Contact:

Associate Professor Steven Ray Wilson, Department of Chemistry

Associate Professor Siri Leknes,  Department of Psychology

PhD Student Ole Kristian Brandtzæg, Department of Chemistry

Scientific publications:

Ole Kristian Brandtzaeg, Elin Johnsen, Hanne Røberg-Larsen, Knut Fredrik Seip, Evan L. MacLean, Laurence R. Gesquiere, Siri Leknes, Elsa Lundanes & Steven Ray Wilson: Proteomics tools reveal startlingly high amounts of oxytocin in plasma and serum. Scientific Reports 6, doi:10.1038/srep31693, Published online: 16 August 2016.

The preprint: A robust peptidomics mass spectrometry platform for measuring oxytocin in plasma and serum. doi: http://dx.doi.org/10.1101/042416

 

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