The double standard of retractions

A growing database of retractions reveals scientific research’s commitment to accountability but highlights flaws in its enforcement

The double standard of retractions

What’s in a word?

In the scientific community, the word ‘retraction’ carries with it a pervasive stigma, often conflated with the idea of an academic death penalty. Retractions, or the pulling of a paper from publication, can tarnish a researcher’s reputation, call into question the legitimacy of a lifetime of work, and dismantle careers.

Outside of the personal realm, retractions alter public perceptions of science.

Last month, the Retraction Watch blog released a Retraction Watch Database. The database is a comprehensive list of retractions in scientific journals since 1923. Out of the 18,000 retractions and notes available on the database, 63 are affiliated with U of T.

What constitutes a retraction?

Science prides itself on being self-correcting, and retractions are a powerful mechanism for that self-correction.

When errors are relatively minor and restricted to a small portion of a publication, a complete withdrawal of the scientific finding is unnecessary and a correction may be issued.

The World Association of Medical Editors defines scientific misconduct as including the falsification, distortion, and omission of data; failure to report misconduct; and the destruction of information relevant to a publication.

Retractions are issued to correct the scientific literature and alert readers of the unreliable conclusions of a paper. According to the Committee on Publication Ethics (COPE), they are “[not] to punish authors who misbehave.”

Yet intent and outcome are not always synchronous. The closure of Toronto-based researchers Dr. Sylvia Asa’s and Dr. Shereen Ezzat’s labs, and the termination of their positions within the University Health Network (UHN), is evidence of how retractions can pose dire consequences to academics’ careers.

Retraction guidelines are inconsistent and could be misinterpreted

Husband-wife duo Asa and Ezzat account for four of U of T’s retractions listed on the Retraction Watch Database. Asa and Ezzat’s cases of scientific misconduct made headlines in the Toronto Star in 2015 and 2016.

They were found responsible for scientific misconduct in the form of material non-compliance. They failed, as principal investigators, to disclose alterations to images and provide preliminary data that matched the published ones in a number of cases of published work.

Asa lost her position as the head of UHN’s Laboratory Medicine Program, the largest program of its kind in Canada, and the UHN imposed sanctions against Asa and Ezzat.

Regarding her 2002 paper, which was one of her articles that was later retracted, Asa told The Varsity that “this was a paper that was almost five years of work. Most of my research starts with a clinical problem, and one of the things I’ve studied is pituitary [tumours].”

“[UHN] claim that two images [of the electrophoresis gels] came from the same one and had been manipulated,” said Asa. “The fact is that we had all the raw data, we had all the original data.”

“Nothing changes anything in that paper, based on the fact that the image was wrong. Patients who have pituitary tumours, for all the people who were involved in the research, all the work that we did is still true,” said Asa. “The results of that paper are no different today.”

The journals in which Asa published her findings were alerted to the irregularities in her research via an outside source.

UHN opened an investigation into Asa’s publications as a result of these allegations, and implicated the pathobiologist in the fabrication and falsification of images. These allegations were challenged in court by Asa and Ezzat, where it was ultimately found that they could not prove who tampered with the images, based on the evidence.

Asa told The Varsity that she felt targeted by the retraction process.

“The retraction process is interesting. It’s definitely necessary. But it has limitations… There have been mechanisms put in place in a lot of different parts of the world, to be more objective and have more standardized criteria for how an investigation is done,” said Asa.

But in a case almost identical to Asa’s, a Montréal researcher was given the opportunity to issue a correction instead of having to retract the entire article.

Cases like this demonstrate the wildly different implementation of retraction guidelines across institutions.

An article in Science suggested that this may be because it is ultimately up to the editors and institutions to determine whether the paper is withdrawn, as COPE only provides guidelines to clarify when a paper should be retracted.

In addition, a study in BMJ Open revealed that retraction notices did not adhere to COPE guidelines in BioMed Central journals. In 11 per cent of retracted articles, the reason for retraction was unclear — six per cent did not state who was retracting the article, while four per cent were retracted simply because not all authors were aware of the paper submission.

The stigma around retractions

A common misconception is that a retraction is invariably associated with data fabrication or scientific misconduct. Yet, of the 63 U of T affiliated papers listed on the Retraction Watch database, only seven are listed for misconduct and eight are listed for fabrication. Fourteen publications have been retracted due to errors in data, attributed to honest error.

Dr. Peter Jüni, Director of the Applied Health Research Centre at St. Michael’s Hospital and professor in the Department of Medicine, has co-authored such a paper.

The publication, a network meta-analysis on the effectiveness of nonsteroidal anti-inflammatory drugs for treating osteoarthritis, was published in March 2017 and retracted in July 2017.

A network meta-analysis compares multiple treatment interventions for a condition directly, using existing comparisons of the interventions in published trials, and indirectly, across different trials.

According to Jüni, research assistants in his team had unknowingly incorporated a duplicate article that had “slightly different results extracted twice” to build their meta-analysis.

“The authors published twice, but they didn’t make it clear that these are the results describing the same population with light differences,” said Jüni. “My colleagues decided to re-run the analysis… and eliminate the duplicate article and… add two new articles that were brought up by colleagues.”

“Now if you include all of those… in an integrated analysis… your numbers will change very slightly,” explained Jüni. “The conclusions of the paper didn’t change at all.”

Jüni recognized the duplicated paper, and the authors were alerted to the two missed trials via colleagues in Ottawa.

Although the error was minimal in nature, The Lancet and the authors agreed it was more feasible to retract and republish the article, as the error ran through different parts of the results and several portions of the paper.

Jüni recognized a flaw in the retraction process that could be exacerbated by the associated stigma of retraction.

“If this is not indexed properly, which was happening at the beginning — the National Library of Medicine just pointed to the retracted article, but it was not clear in PubMed or Medline that this was basically paired with a republication — then it could mean potential questions regarding your reputation,” said Jüni. “The question is then, should we call it differently?”

“Would I prefer to have another label associated with it? Yes, because of the associated stigma — but I don’t think it will happen and I think the important part is that the indexing system changes their way of reporting it. It’s not optimal, but honestly, I can live with it. And obviously I have to live with it,” continued Jüni.

Despite the sting of retractions and the potential fallout, Jüni believes that researchers have an obligation to self-report mistakes.

“You need to live as a leader, in a culture where everybody admits [they don’t] know or [made] a mistake. I need to start with that as the Director of Applied Health Research — if I don’t live it, my people don’t dare admit mistakes. We need that to make research better. That’s part of the quality assurance process.”

It is clear that the retraction process is flawed — it holds too much stigma, does not implement guidelines consistently, and fails on many occasions to communicate to the public the reasons for paper withdrawal. However, it is currently the only system we have to correct the literature and protect scientific endeavours.

What implications do retractions have for scientific research?

Trudo Lemmens, professor and chair of the Department of Health Law and Policy at the Faculty of Law, believes that the increase in the number of retractions may be due to a growing concern around scientific integrity due to a growth in scientific publications over the years.

Science reports that an increase in retractions could be attributed to more comprehensive oversight from scientific journals. Though editorial practices differ from journal to journal, a rise in retractions hints at stricter editorial practices.

In 2009, COPE published guidelines that suggest a publication should be retracted if the findings are unreliable due to scientific misconduct, plagiarism, duplication, or honest error. By 2015, these guidelines were adopted by two-thirds of 147 high-impact journals, and have helped standardize the retraction process.

Editor’s Note (November 27): A previous version of this article incorrectly suggested that Jüni’s assistants were the ones to discover the duplicate.

The Screen Project slashes wait times for breast cancer screening

Women’s College Hospital initiative tests for BRCA1 and BRCA2 gene mutations

The Screen Project slashes wait times for breast cancer screening

Government-sponsored screening for breast and ovarian cancer in Canada can take up to a year to occur and can be denied based on a patient’s risk profile. To shorten wait times and offer universal testing, the Familial Breast Cancer Research Unit at Women’s College Hospital (WCH) has introduced The Screen Project initiative, which aims to make screening universally accessible to patients over 18 in Canada, and hopefully produce better patient outcomes.

The Screen Project has discounted its regular screening price to $99 USD for October, which is Breast Cancer Awareness Month. Ordinarily, the research unit screens patients for $165 USD. Results are expected within two to four weeks.

Why isn’t government-funded screening universal?

According to Dr. Steven Narod, Director of the Familial Breast Cancer Research Unit at WCH, screening through Canada’s universal healthcare system costs around $2,000–3,000 and wait times can last up to one year. As a result, as little as three per cent of women are eligible for the test per year.

But in 2017, the Familial Breast Cancer Research Unit found that commercial genetic testing could be completed in a shorter amount of time and for a fraction of the cost by sending samples to Veritas Genetics, an American genetic sequencing laboratory with whom the Unit has partnered for The Screen Project.

Veritas Genetics tests for BRCA1 and BRCA2, which are gene mutations associated with breast cancer. Women with a BRCA mutation have up to an 80 per cent lifetime risk of breast cancer and a 40 per cent lifetime risk of ovarian cancer versus a 12 per cent and a 1.3 per cent lifetime risk for women without the mutation, respectively.

How does the project work?

To provide a genetic sample for testing, patients order a genetic test kit from Veritas Genetics, provide a saliva sample, and then ship the kit and sample back to the Veritas Genetics lab. The lab tests the sample and releases the results to the patient and the Familial Breast Cancer Research Unit.

Patients with a negative test result receive an email or letter of notification. But patients who produce a positive test result receive an email or letter, as well as a personal phone call from a genetic counsellor at the Familial Breast Cancer Research Unit.

According to Narod, The Screen Project’s offer of “genetic testing for breast and genetic testing for ovarian cancer” for $165 USD is “ethical and wise,” since it is affordable for most Canadians.

However, Narod notes that the results of The Screen Project raise an ethical concern of whether it is “proper, right, and ethical to offer healthcare services outside of what’s insured by the public healthcare system.”

As The Screen Project continues, Narod plans to track the interest in genetic testing for breast and ovarian cancer in Canada, patient satisfaction afterward, and the actions that the project and patients choose to take to reduce their risk of breast and ovarian cancer following a positive test result.

For dance flies, size does matter

UTM study shines light on sexual differences in animal mating behaviour

For dance flies, size does matter

For female North American dance flies, size definitely matters.

A recent UTM study discovered that, for North American male dance flies, sexual attraction is highest when female mates display large inflatable abdominal sacs. 

The study was published in Proceedings of the Royal Society B by UTM postdoctoral fellow Rosalind Murray, UTM biology professor Darryl Gwynne, U of T biology lecturer Jill Wheeler, and University of Stirling biologist Luc Bussiere.

To attract male dance flies for fertilization, the researchers found that female flies display signs of sexual ornamentation. The female flies use valuable energy reservoirs to expand their abdominal sacs, which is appealing to their male counterparts. 

In cases where female dance flies have smaller abdominal sacs, they attract males flies through larger leg scales.  

When discussing the reasoning behind her study, Murray said she “wanted to do an experiment to see if these ornaments were actually attracting the males and if they were working in the same way we typically see male ornaments — so, bigger is better.”

Why are the female flies using large amounts of energy to attract their male counterparts? 

According to Murray, the male flies provide them with a “food gift,” because the female flies have lost their ability to hunt, “so the males go hunting and they bring, usually another fly or insect. They kill it and they present it to the female in exchange for mating.”

The research took place over a 10-day period on an island in Credit River last June. North American dance flies are peculiar creatures that only appear for one hour at dawn and another hour at dusk.

As such, to complete the field research, Murray would wake up before sunrise to study the flies for an hour when they came out.  

During the day, Murray would analyze the data collected from the morning, and then she would venture out again at 8:30 pm to study the flies until sundown.

To test her theory, Murray created models that imitate female shapes and examined the impact of the two ornament types.

The research is particularly significant because it demonstrates a stark shift in our understanding of the animal kingdom. 

Typically, research has suggested that male animals use their energy to attract female counterparts. Much of Charles Darwin’s research, for example, focused on this phenomenon of sexual selection between mates.

However, Murray and Gwynne’s research turns this idea on its head.

“There are certain ways across animal kingdoms that males and females behave… It’s rare that you do find the vice versa, whereas in these flies, the subject of the paper, females are displaying very male-like traits,” Gwynne said. “They have reversed roles.”

Within the field of evolutionary biology, Murray’s study is the first that demonstrates this kind of female sexual ornamentation. “It’s such a bizarre system,” Murray said. 

“We’re looking at similar questions among many species of dance flies, thinking about how different species have evolved these ornaments.” 

With files from Srivindhya Kolluru

Research by all, for all

The underrepresentation of women and racialized folks in academia indicates the importance of promoting equity and diversity at U of T

Research by all, for all

It was recently announced that U of T will implement 49 new recommendations from the Equity and Diversity in Research and Innovation Working Group to foster more equity in every stage of research and academia — from ensuring diversity in committees that provide awards and funding to requiring further training in unconscious biases.

This is certainly exciting, especially since the announcement comes with concrete steps to fulfill its vision, which makes this promise feel substantive rather than empty. Assuming that these measures are put into place and followed, real progress is on the horizon.

Sadly, this change is urgently needed in academia. Study after study has shown that the field not only consists of overwhelming numbers of white and male academics, but it is also reluctant to change itself.

For example, in a 2012 study, professors in biology, chemistry, and physics departments at six universities across the US were given identical applications for a lab manager position, with some applicants using female names and others using male names. The male applicants were rated as more “hireable” and competent, and offered a larger starting salary.

In 2016, the Dean of U of T’s Faculty of Medicine, Dr. Trevor Young, revealed some sobering statistics about the racial and socioeconomic makeup of medical students and faculty: Black, Filipino, Latinx, and Indigenous students were “woefully under-represented,” and, in 2013, 75 per cent of the faculty were white.

To even produce these statistics is surprisingly difficult. In 2017, CBC reported that despite the claims of many Canadian universities as pro-diversity, very few actually have any data about the racial demographics of their students. This allows universities to plead ignorance about any kind of discrimination on their part, and allows them to continue a charade of racial blindness.

Many may fight back against these measures as being ‘discriminatory’ toward white men in favour of minorities and underprivileged folks, or suggest that the best solution would simply be to approach hiring, funding, and the like with blindness toward gender and racial considerations. To the former point, it is worth noting that none of the recommendations even suggest or imply discrimination toward white men.

To the latter point, I would say that this is impossible thanks to unconscious biases, which means that even those with the best of intentions still discriminate. In the 2012 study, it is highly unlikely that the faculty involved all held genuine contempt for women, but it is far more likely that they had absorbed societal ideas about men and women in science, and reflected them in hiring practices.

To go beyond the simple fact that more people of diverse backgrounds should have opportunities in academia and research, it should be noted that the type of research that would be conducted with more people who are not white men could be badly needed, or done with a genuine cultural sensitivity that may not be present otherwise.

A person with a particular racial background may have an interest in a research topic that affects them more than it does the dominant race. Someone who is part of an underprivileged community, especially one that has a history of mistreatment in research, may be able to connect with their own community and understand how to conduct research with them better.

Research in every field, from medicine to anthropology, has a tainted history of ignoring the needs and wishes of the communities they encounter, which can lead to dark consequences. Look no further than eugenics as a field, the Tuskegee syphilis experiments, or the US Army working closely with anthropologists to finetune their strategy in Afghanistan.

Paula Rochon, Vice-President of Research at Women’s College Hospital, was part of the working group and reported last yearthat, because women were underused as research subjects in a study on dementia, it is unknown how certain dementia medications affect women, despite the fact that most elderly people with dementia are women. More female researchers, in that case, would have been more likely to push for more female subjects.

And we can extrapolate that to a larger scale. If most researchers are white men, with funding being granted by other white men, and the findings are presented to white men with nobody else in the room, the research would suffer by only focusing on certain issues and their effects on certain people.

No matter your personal identity, I hope that advocating for equity and diversity in academia and research is something we can all celebrate. These steps get more people from diverse backgrounds to be a part of every step of the process. This means more opportunities for more people, better research, and positive outcomes for everyone.

Adina Heisler is a fourth-year Women and Gender Studies and English student at University College.

Researchers identify a Neanderthal-Denisovan hybrid

The discovery sheds light on our human ancestors

Researchers identify a Neanderthal-Denisovan hybrid

A single bone fragment can reveal thousands of years of human history.

In a study published in Nature, a team of researchers, including U of T Professor Bence Viola, identified a hybrid between two extinct lineages of hominids — Neanderthals and Denisovans — in a bone fragment.

Neanderthals lived on earth about 40,000 years ago, and, along with modern humans, they evolved from Homo erectus. Denisovans diverged from Neanderthals, but little is known about them other than bits of information recovered from bone fragments of their extremities, found in a Denisova Cave in Siberia’s Altai Mountains.

This is why, when researchers found a bone fragment in the Denisova Cave in 2012, they didn’t give much thought to the finding; it looked like all the others, an ordinary and tiny piece of what was thought to be part of a bear or lion.

After all, when a site is being excavated, many items are found, including pieces from animals and insects.

“There are 100,000 bone fragments found at a time and this particular one had a length of only 2.5 centimetres long, roughly the size of a toe bone,” said Viola.

A few years following the discovery, the fragments were analyzed for collagen. Finding a long bone fragment gave researchers an advantage for conducting DNA extraction techniques because of its morphology; it preserves better and allows for further manipulation.

“The bone was also discovered to have an acid coating which suggested it was digested by hyenas,” added Viola. The fact that DNA evidence survived this process makes this discovery even more extraordinary.

The bone was determined to belong to a female around age 13. This teenager died 90,000 years ago and was the offspring of a Neanderthal mother and Denisovan father.

Viola couldn’t believe it.

Based on previous studies, it was assumed that Neanderthals and Denisovans occasionally interacted, but interbreeding between the two hominins was thought to be rare.

This breakthrough informs researchers that interbreeding could have contributed to the gene flow, or transfer of genetic information, and it is now evident in the bone fragment.

The fragment is also evidence that the two species were in the same region at the same time.

Interbreeding is a result of various factors, such as an attempt to colonize certain areas. The discovery could help shape our understanding of hominin interactions and forms the basis to determine further benefits to interbreeding.

As such, this finding allows researchers to try and understand the lives of our closest ancient human relatives.

A loophole in the cancer cell cycle is found

Researchers uncover an inhibitor that could halt cancer progression

A loophole in the cancer cell cycle is found

YAP and TAZ are proteins that have long been recognized for their role in regulating transcription — a process in which the information in DNA is copied into RNA — and are particularly relevant in cancer development.

A recent study in Nature Communications led by Mandeep K. Gill in U of T’s Department of Biochemistry identified NUAK2 as a gene that could control YAP/TAZ activity.

In normally functioning cells, YAP and TAZ are responsible for forming and regenerating tissues. In tumours, however, these proteins are able to initiate and metastasize, or spread, cancer cells to other parts of the body, as well as initiate the tumours.

“The relatively recent discovery (roughly 10 years) of the so called  ‘Hippo pathway’ which normally acts to limit excess cell growth and the demonstration that it is turned off in most cancers has provided a new target for the development of therapeutics,” explained Liliana Attisano, a principal investigator of the study also from the Department of Biochemistry, in an email to The Varsity.

The Hippo pathway is a process that controls tissue and organ development in mammals, especially in their size, by regulating cell growth and death, and controls the transcriptional activity of YAP and TAZ proteins.

The pathway can be activated by various factors, after which it engages its core cassette — a subunit made of enzymes known as kinases, which are involved in the movement of phosphate groups, or phosphorylation.

When a cascade of phosphorylation — the addition of a phosphate group — occurs in the cassette, YAP and TAZ are marked with phosphate groups and are targeted for degradation.

When the Hippo pathway is inactive, however, YAP and TAZ accumulate in the nucleus and latch on to the DNA-binding proteins in there, which can lead to cancer cell proliferation. 

Attisano and her team discovered NUAK2 was found to encode a protein that results in even more YAP and TAZ getting into the cell’s nucleus to further promote abnormal cell growth.

The researchers started by conducting studies in breast cancer cells and were able to identify  the kinase NUAK2 as a positive regulator of YAP and TAZ activity.

According to the study, “NUAK2 functions in a kinase-dependent manner to promote nuclear YAP/TAZ localization and activity” and promotes YAP and TAZ activity in a positive feedback loop.

A decrease in NUAK2 is therefore found to reduce transcriptional activity and the quantity of YAP and TAZ in the nucleus. As well, kinase-deficient NUAK2 was found to restore YAP and TAZ localization in the nucleus, which deemed NUAK2 an activator of YAP and TAZ activity.

“We found a way to restore the activity of the pathway (by removing or blocking NUAK2 activity),” wrote Attisano.

A lack of NAUK2 in cells showed a reduced cell growth and robust tumour growth in mice.

Tests were conducted on bladder cancer cells to determine the implications for human tumour progression. Larger increases of NUAK2 were found in high-grade samples that came from patients who had experienced a relapse.

These findings could be applied to cancer treatments as blocking the expression of or inhibiting NUAK2, YAP, and TAZ appears to restore Hippo pathway activity and cell growth, thus limiting tumour progression.

“There is still a long road ahead,” wrote Attisano. “But the next step would be [to] develop specific and potent compounds that can be tested in mouse and human organoid models with the long-term goal of… identifying a drug that can be used in patients.”

Explainer: Open Access in science

What the open access movement means for Canada and beyond

Explainer: Open Access in science

The European Union recently proposed Plan S, which aims to make all government-funded research open access (OA) and was accepted by 11 prominent funding agencies across Europe.

This initiative would deter researchers from publishing in traditional-style journals, such as Nature and Science, and attempts to circumvent issues perpetuated by paywalls so that information is more readily available to the public.

Open access refers to any scholarly research that is free, easily accessible, and often available online.

A brief history

The OA movement has been around since physicists and computer scientists began archiving data online, as early as the 1970s.

This way of using the internet to store and organize data gained immense popularity among librarians worldwide.

As the internet gained momentum, subscription costs for traditional journals started to rise and, consequently, neither public nor academic institutions could afford to access much of the research that was available. This resulted in a problem now known as ‘serials crisis.’

As a result, publishers were forced to drastically lower prices and provide grants to under-financed institutions and less economically stable countries.

Since then, the movement for OA publications has continued to grow, and has garnered both support and disdain globally. 

Types

OA publishing is widely classified into three main types: Gold OA, Green OA, and Hybrid OA.

Gold OA articles are immediately available online after publishing, but researchers must foot the costs of processing the article, including editing and peer review.

Doing so eliminates subscriptions and subsequent paywalls, but article processing charges (APCs) could present a large financial barrier to already underfunded research projects.

Green OAs have no APCs and are published in traditional journals, but are ‘self-archived’ in repositories, where they become available after an embargo period set by the publisher. The repository can be institutional or external and is often subject-based, which allows the general public to navigate a vast body of research more easily.

Hybrid OAs are the most prevalent and are offered by publishers that function as traditional journals.

Hybrid OAs are seen as a transitionary model that allows the copyright to stay with the author, giving them the right to publish the final version of the article without an embargo period.

Open access in Canada

Within Canada, there are three major federal granting agencies: the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, and the Social Sciences and Humanities Research Council. The three have come together and adopted a tri-agency OA policy that aims to expand the audience for the research they fund.

Canada has set an international precedent with this action and is working toward creating a more accessible scientific community.

Open access at U of T

The University of Toronto has adopted a similar policy and has readily available resources to help researchers make their findings OA. The initiatives introduced include TSpace, Open Access Week, Digital Special Collections, and Journal Production Services. University of Toronto Press also has four OA journals and continues to expand its collection.

Beyond Canada

As with any new movement in science, there are many detractors from the OA movement. In an industry worth more than $25 billion, publishing companies see OA as cutting a hole in their pockets.

The reputation of journals and the ‘publish or peril’ mentality have contributed to a robust industry, and many researchers view publishing in prestigious journals as the only way to further their careers.

The reputation that journals, such as Nature, carry in the scientific community make their demise seem unlikely.

Regardless of type, OA has garnered immense support worldwide. For government-funded research, it is a way of giving taxpayers a return on their investment. The movement could help combat misinformation, provide data for mining and commercial purposes, and help shape public policy.

The increased exposure associated with publicly available research also helps scientists in underfunded institutions gain access to new information. This results in a higher citation rate, which  is a key measure of an article’s value.

Despite protests, the OA movement is revolutionizing how research is shared to the public and among fellow researchers.

Insulin may ward off infections

University Health Network researchers find insulin could play a role in the immune system

Insulin may ward off infections

It was Frederick Banting’s co-discovery of how to extract insulin in the early 1920s at U of T that continues to save millions of lives across the globe, providing hope to patients suffering from diabetes who, in previous years, had none.

For Dr. Sue Tsai and Dr. Dan Winer at the University Health Network (UHN), insulin is the gift that keeps on giving.

“In [our] field a lot of people are looking at how obesity causes inflammation,” said Tsai. “But no one really knows it affects the immune system when it comes to infectious diseases, or cancer, because so many things are altered [and] your hormones are all dysregulated.”

Insulin’s role in diabetes is well-researched, but little is known about the role it has in regulating T cell function and what leads T cells to stop responding to insulin.

Tsai wanted to determine what factors cause obese individuals to have a reduced response to vaccinations, develop more infections, and be more likely to develop cancer.

They narrowed their target to insulin, because individuals become resistant to it when they become obese.

Tsai, a postdoctoral fellow at UHN, and Winer, an Assistant Professor in U of T’s Department of Laboratory Medicine and Pathology, have uncovered an insulin signalling pathway that elicits a response from infection-fighting T cells when they are activated.

Insulin, a pancreatic hormone, promotes glucose uptake via downstream signalling pathways. These pathways involve the binding of the insulin hormone to an insulin receptor (INSR).

Immune cells, such as B cells and T cells, that protect the body against infection also possess this receptor. Tsai and Winer hypothesized that the binding of this receptor would stimulate T cell activation and proliferation, leading to a strong and immediate immune response.

In their study, Tsai and her colleagues compared T cell function in mice without the INSR to those with the receptor.

“We found that T cells [without INSR] become less functional, and when we give the mice influenza [H1N1], they do worse,” explained Tsai. “They lose more weight and then they have a weaker immune response against the influenza.”

INSR played an integral role in maximizing the potential function of the T cells in mice by increasing their nutrient uptake and in turn generating energy through ATP production during inflammation and infection.

The researchers’ findings provide some reasoning as to why vaccines in obese individuals may not be as effective. Many obese individuals are insulin-resistant and, as shown in this study, could therefore have a weaker T cell response.

T cells are integral to the efficacy of a vaccine, as they recruit infection-fighting antibodies and aid in immunological memory.

Tsai hopes to continue exploring the link between insulin and immunity, and is currently investigating insulin signalling in B cells. She believes the findings of these studies could have wide-ranging applications.

“The most obvious thing is influenza vaccines. How can we develop a vaccine, and what additional signals can we add to the vaccine to get them to work better in individuals who are insulin resistant?” said Tsai.

“Also, tumour immunotherapies. Do obese people respond to these therapies differently than non-obese people and does insulin resistance play a role in that?”

In the future, the insulin signaling pathway could also be used to study and find ways to ‘boost’ the immune system and develop vaccines that would work more effectively in obese individuals.

Tsai’s findings were published in Cell Metabolism last month, almost a century after the discovery of insulin.