Of the three winners of the 2024 Lasker Prize for Clinical Medical Research, Svetlana Mojsov, a scientist at Rockefeller University, is undoubtedly the least present. Although she participated in the original groundbreaking research of GLP-1, deciphered the true GLP-1 activity, and was able to synthesize experimental materials in large quantities quickly and accurately, she had an advantage in the fierce competition, but in the following 30 years, she disappeared into the dust: the GLP-1 drug became a big hit and won many awards, but her name was not among the winners; Now in her early 70s, she is still a research associate professor. It wasn't until a year ago that her legendary past was reported by the media.
Compile | leaflet
In June, Svetlana Mojsov returned to New York with her husband. Due to the delay of her flight, she took the time to check her email and saw an email from Joe Goldstein. The latter was the winner of the Nobel Prize in Physiology or Medicine in 1985 and is today the chairman of Lasker's selection committee for medicine.
Goldstein's email brought good news: Mojsov became one of three recipients of the 2024 Lasker Award for Clinical Medical Research. They were awarded for the discovery and development of the GLP-1 drug, which revolutionized the treatment strategy for obesity [1]. The Lasker Prize is one of the most important awards in the field of biomedicine in the world, and is also known as the "Nobel Prize vane". In the past 20 years alone, a total of 32 Lasker Prize winners have gone on to win the Nobel Prize. Coupled with the great contribution of GLP-1 drugs in the treatment of diabetes and obesity, there is more and more speculation that it may win the Nobel Prize.
In fact, only a year ago, Mojsov's outstanding academic contributions were little known even in the scientific community. It wasn't until Science, Nature and some media reported on her that a legendary scientific research story was made public.
Svetlana Mojsov研究副教授丨来源:洛克菲勒大学网站
Forgotten pioneering contributions
The other two scientists who won the award were Joel Habener, an endocrinologist at Massachusetts General Hospital (MGH) in United States, and Lotte Bjerre Knudsen, a Denmark scientist at multinational pharmaceutical company Novo Nordisk. Habener was already a leader in the field of GLP-1 research in the 80s of the 20th century, and has received numerous awards [2] to this day. Knudsen is the chief scientific advisor of Novo Nordisk, and since the 90s of the 20th century, he has led the team to "break new ground" in the field of diabetes and obesity drug development [3].
Compared to them, Mojsov has been silent for nearly 30 years in various scientific narratives related to GLP-1, diabetes, and obesity, and it is only in 2023 that she has bravely spoken up for herself and finally won public recognition from the academic community.
Back in the '70s, Mojsov from the former Yugoslavia enrolled at Rockefeller University for graduate studies in the laboratory of the famous chemist Bruce Merrifeld. She specializes in glucagon, a hormone released by the pancreas that detects insulin: insulin lowers blood sugar, while glucagon raises blood sugar. Therefore, scientists believe that inhibiting glucagon may help treat type 2 diabetes. At the time, Merrifield's lab had come up with a groundbreaking method for synthesizing glucagon, and Mojsov mastered the synthesis technique, and she stayed in the lab as a postdoc to improve her technique.
While still in graduate school, Mojsov met her future husband, Michel Nussenzweig, an already renowned immunologist at the time. He often invited Mojsov to tea to help her relieve the pressure of essay writing. By the early 80s, Nussenzweig had completed his residency at MGH, and Mojsov had joined the hospital's endocrinology department as an instructor, while she was also in charge of a new department that synthesized peptides for scientists in the department. As long as a certain amount of peptide is synthesized on demand every day, this work does not take much time for Mojsov. As a result, she had the opportunity to conduct her own research work, and she already had a clear goal in mind: a mysterious peptide called glucagon-like peptide-1 (GLP-1).
Also in the 70s, Habener was already a rising scientific star in the field of endocrinology. His team had been studying key hormones in the anglerfish pancreas, including glucagon, by freezing the hormone-producing islet cells to clone proglucagon.
In 1982, the team published a paper [4] in which it was reported that the fish gene encodes a large precursor protein, which is cleaved and processed to form glucagon, and there is also an amino acid fragment embedded in the glucagon, similar to glucagon, which later became known as GLP-1. In addition, the amino acid sequence of GLP-1 shares certain characteristics with gastropin (GIP), which was the only known member of incretins that was rumored to belong at the time, and scientists believed that incretin had the potential to treat type 2 diabetes, but experimental results showed that its use was not effective in affecting insulin levels in diabetic patients.
So, both Habener and Mojsov wondered if the GLP-1 was any different. The first problem to be solved is to determine where in the body the peptide activity is produced. In his small office, Mojsov takes a closer look at the 37-amino acid chain in the mammalian GLP-1 sequence. Based on its similar properties to glucagon, she boldly hypothesized that the chain of 31 amino acids from site 7 to site 37 in the large GLP-1 peptide could be an incretin. So, on a piece of paper printed with the amino acid sequence of glucagon (see figure below), she took notes on the function of GLP-1 and resolved to prove her hypothesis [5].
这张手写下GLP-1功能的纸用于1992年Mojsov个人发表在《国际肽和蛋白质研究期刊》（International Journal of Peptide and Protein Research）上的论文中。 丨来源：STAT NEWS
In order to look for 7-37 amino acid fragments in the gut, Mojsov needs fish with antibodies, because the peptide itself may be present in extremely tiny doses, which are difficult to detect, and the antibodies are able to mark the location of the peptide more clearly. She first manufactured GLP-1 in large quantities and stored it in glass bottles; Subsequently, different fragments of the peptide were injected into the rabbits used for experiments and left for two months to allow the antibodies to multiply as much as possible in the rabbit's blood. Finally, she collected a blood sample from the rabbit's neck artery and isolated the antibodies. All of this is done by Mojsov on her own, and her years of experience in the laboratory make her very comfortable with it.
Downstairs in Mojsov's office, Habener's team began exploring the biology of GLP-1. In 1984, the lab recruited Daniel Drucker, a postdoctoral researcher tasked with determining which cell types could produce such peptides. As a novice endocrinologist who had never had laboratory experience, Drucker quickly got into trouble because there was no one to assist or guide him in his work.
Although Habener and Mojsov each conducted their own research, Habener clearly knew what Mojsov was doing. So, at Habener's suggestion, Drucker approached Mojsov and talked about cooperation. At this point, Mojsov said that he had made antibodies against different GLP-1 fragments and had a method to detect the presence of GLP-1 fragments. Next, Mojsov joined forces with some researchers in Habener's lab to track different GLP-1 peptide fragments within various tissues of mice using Mojsov's method. Despite this, Mojsov remained a solo researcher for most of the time. Eventually, she discovered the active GLP-1 (7-37) amino acid chain in the gut of mice.
In 1986, Mojsov and Habener were collaborators in a paper [6] detailing the presence of GLP-1 (7-37) amino acid chains in the gut. Today, the paper is recognized as an important milestone in the development of the field, with Mojsov taking the first place and Habener lasting as the corresponding author.
The second question then arises: whether the 7-37 amino acid chain of GLP-1 in the gut is biologically active. Specifically, whether it triggers the release of insulin from the pancreas. Using GLP-1 synthesized by Mojsov, Drucker led a study that demonstrated that [7]GLP-1 does indeed promote insulin secretion in rat islet cell lineages. Immediately afterward, Habener wanted to further test the effects of GLP-1 on the whole organ, and he contacted his friend, endocrinologist Gordon Weir. The latter developed a model of rat pancreas, which survived in an acrylic incubator filled with oxygen, and the researchers measured the insulin levels of the model animals every minute at room temperature. When Weir was injected with GLP-1 synthesized by Mojsov, it was found that the amount of insulin output increased. Subsequently, even if the amount of peptide injected was reduced, even in very small doses, the researchers unexpectedly observed the same effect.
Mojsov measured GLP-1 intake and confirmed that the peptide was consistent with the insulin response. The two hormones "go hand in hand and increase at the same time." "It was a wonderful experiment." Finally, the paper was published in The Journal of Clinical Investigation in 1987 [8] with only three authors, with Mojsov still in first place and Habener last. Weir commented that this paper is the most important research he has assisted.
After a series of animal studies in the model, Habener's team continued to move towards human testing, working with Mojsov and David Nathan, a diabetes expert at MGH [9], who injected peptides into healthy subjects and diabetics and found that GLP-1 promotes the release of insulin when blood glucose levels rise. The study, published in the journal Diabetes Care in 1992, is arguably Mojsov's last collaborative study on GLP-1.
GLP-1 drugs are gradually "becoming gods"
From the 90s, Mojsov's research career took a turn for the worse. Her husband, Nussenzweig, received a job offer from Rockefeller University for an attractive pay, and he readily agreed. So, Mojsov returned to New York with her husband and started a new chapter in her life full of hope.
Her association with GLP-1 drug development was interrupted. Since then, GLP-1 research has advanced by leaps and bounds, eventually providing a powerful new weapon for humanity in the fight against disease.
At that time, in addition to Habener's team, scientific research groups in other countries were also actively exploring the effects of this peptide on human health, and more and more studies were published: Jens Juul Holst, professor of medical physiology at the University of Copenhagen in Denmark, and Michael Nauck, an endocrinologist at the Ruhr-Universität Bochum in Germany, co-led the study. 10], GLP-1 has also been found to normalize blood sugar levels in diabetic patients. In addition, Holst's team investigated 20 healthy young men [11] who received GLP-1 intravenous injections after a hearty breakfast, and by lunchtime the subjects were less gulp-free than the placebo control group. The team at Hammersmith Hospital in London, United Kingdom, also came to a similar conclusion [12], injecting GLP-1 into the brain of rats can strongly inhibit the urge to eat, resulting in loss of appetite. This also seems to hint at another direction of GLP-1 application transformation in the future.
Continued reporting of basic scientific research has led pharmaceutical companies to see new potential in the development of GLP-1 drugs for the treatment of diabetes. However, in the new era of rapid development of biomedicine, it took nearly 20 years from the successful discovery of GLP-1 in the laboratory to the final drug in the hands of patients with peace of mind.
In 2005, the first GLP-1 drug for type 2 diabetes, Byetta, was approved, but the key ingredient is synthetic exenatide (exendin-4), which is derived from the exendin-4 found in the venom of the Lizard sylvestris sir, which is similar in structure and function to human GLP-1 and does not degrade after being injected into the body for several hours [13].
Five years later, Novo Nordisk used the natural GLP-1 molecule as a template, replaced one amino acid and added a 16-carbon palmitoyl side chain to create a GLP-1 analogue, liraglutide (Victoza) [14], which was subsequently approved for the treatment of diabetes in United States. Liraglutide not only maintains the physiological characteristics of natural GLP-1, but also has a high-efficiency and long-lasting hypoglycemic effect, and is not easily degraded by degrading enzymes. Moreover, the half-life period is as long as 12 to 14 hours, and for diabetic patients, only 1 subcutaneous injection per day can exert a good hypoglycemic effect.
More easter eggs are yet to come, and the application of GLP-1 drugs is not limited to diabetes treatment. As mentioned earlier, GLP-1 has a variety of effects on various organ systems, the most relevant of which is reduced appetite and food intake, leading to weight loss. This is a very wonderful side effect that has been discovered in clinical trials and can be fully exploited to solve another public health crisis facing modern people: overweight or obesity.
Since the 60s of the 20th century, various short-term weight loss drugs, such as phentermine, benzylfilamine, and diethylacetone, have appeared, but long-term safety data are blank [15]. Until the 90s of the 20th century, the weight loss drug "Fen-Phen" caused serious health problems such as fatal heart valve disease and pulmonary hypertension [16], and people never found a safe and effective weight loss drug. As a result, pharmaceutical companies are making every effort to develop this new therapeutic function of GLP-1 drugs. Finally, in 2014, Novo Nordisk's liraglutide became the first obesity treatment drug approved by the United States Food and Drug Administration.
In 2022, its next-generation GLP-1 drug, semaglutide, continued to be approved for diabetes treatment (marketed under the name Ozempic) and weight management (under the name Wegovy). And it quickly became popular in the market. According to statistics, 1.7% of people in the United States have prescribed Ozempic or Wegovy in 2023. Unlike previous medications, semaglutide only needs to be injected once a week. According to a study published in the New England Journal of Medicine [17], subjects who took semaglutide lost an unprecedented 15% of their body weight over a period of about 16 months, but also reported common adverse effects: nausea and diarrhea.
As of 2023, a total of 11 GLP-1 drugs have been approved worldwide for the treatment of type 2 diabetes and obesity, including exenatide, lisinatide, dulaglutide, benaglutide, liraglutide, semaglutide, tirpatide, and others [18]. In the same year, GLP-1 drug therapy was also successfully listed as one of the top 10 scientific breakthroughs of the year by Science [13].
Some GLP-1 agonist drugs commonly found on the market, source: medpagetoday.com
No more silence, finally recognized
Unlike the popularity of GLP-1 drugs, Mojsov's research career has been flat since he left the relevant R&D field. She came to Rockefeller University with her husband as a research assistant professor in the lab of immunologist and future Nobel laureate Ralph Steinman. At that time, Mojsov also had a toddler and a baby waiting to be fed. Like many women in the workplace, she had to work harder to balance raising her children with her career.
With a grant from the United States National Science Foundation, she shifted her subject to studying the GLP-1 biology of fish, working with scientists studying glucose metabolism in fish. At the same time, she helps other researchers in the lab with peptide biology, and she finds that working with junior scientists brings a different sense of accomplishment. She believes that science is collaboration, and everyone makes a valuable contribution to science, whether they are young scientists, junior scientists, or senior scientists. She does not recognize the so-called senior scientists as the biggest contributors to cutting-edge scientific knowledge, and junior scientists as auxiliaries.
Steinman's lab became a stable research base for Mojsov, where she remained for more than 20 years until Steinman's death in 2011. Today, Mojsov is a research associate professor at Rockefeller University, but instead of leading the lab herself, she collaborates with different scientists.
Mojsov has always been proud of his basic research on GLP-1 at MGH and has been monitoring developments from time to time. In 1996, she learned from an employee at a biotechnology company that the GLP-1 patent had been granted several years earlier.
Soon, she found two patents that had been registered in 1992 for a "fragment" and a "derivative" of GLP-1 that promoted insulin secretion. A third patent is also pending. However, Habener was listed as the sole inventor in all patents, and Mojsov had nothing to do with it, and she was quite shocked.
So, Mojsov decided to hire a law firm to help him fight for the rights of co-inventors. After several years of struggling with MGH's patent department, between 2004 and 2006, MGH agreed to amend four patents (including a fourth granted to Habener in 2005) to list Mojsov as a co-inventor, and the United States Patent and Trademark Office officially confirmed the change. The fifth patent was granted directly to the two scientists in 2006.
Mojsov said MGH agreed to give her one-third of the royalties for the drug, and Habener received the rest. She declined to give the exact amount, but said: "For an academic, it's not bad, there's nothing to complain about." ”
Although in terms of interests, Mojsov reaped the rewards he deserved for his pioneering contributions; But in terms of reputation, she was still buried for a long time.
The success of GLP-1 has put the scientists behind the scenes into the public eye, and it has won various medical awards. In 2017, Habener, Drucker, and Holst co-won the Harrington Prize for Innovation in Medicine, which recognizes three scientists for "discovering and translating incretin into transformative new therapies" [19]. In 2020, they received the Warren Alpert Prize from Harvard Medical School · [20]. In 2021, the Canada Gairdner Award, an internationally prestigious biomedical research award, was also awarded to the three scientists [21].
The discovery of GLP-1 is mentioned in all of the award-winning presentations, however, Mojsov's name does not appear in any of the lists of relevant scientific awards, and her outstanding contributions are forgotten.
Jeffrey Flier, former dean of Harvard Medical School, acknowledged that scientific prizes are an important way for the academic community to recognize, and that normally, award committees focus on scientists nominated by scientific institutions and peers, and that Mojsov is likely to be at a disadvantage if he does not hold important positions and have no lasting influence in the GLP-1 research process.
Even if Mojsov was absent from the translational development phase of GLP-1 for various reasons, it does not mean that all her efforts in the initial basic research stage can be erased. Drucker, now a professor at the University of Toronto, acknowledges that Mojsov's important contributions should not be overlooked. Habener also always remembered Mojsov as an important collaborator: "She was involved in the first pioneering research that deciphered the real GLP-1 activity. Her ability to synthesize large quantities of peptides quickly and accurately gives us an edge over the competition. ”
In addition, Mojsov's silence for more than 30 years may have something to do with her personality, she is a very privacy-conscious person. Until last year, she had barely told anyone about her involvement in GLP-1 research. After learning all about this, her graduate classmate, the chemist George Barany, who had been friends for nearly 50 years, Barany's brother Francis Barany, who was also a chemist, and some of Rockefeller's colleagues all supported her in speaking out. "What happened to Mojsov is a cliché in the scientific community, there are no bad guys here, but she really doesn't get the recognition she deserves," Francis Barany said. ”
Although it was not easy for Mojsov to talk openly about herself, she finally stood up and tried to speak for herself. At the same time, Habener, Drucker, and Holster all confirmed Mojsov's important contributions, and Harbener expressed his support for Mojsov and was on the same side as her.
In September 2023, Science published a news feature detailing her history and achievements in the development of GLP-1. At the end of the same year, Nature selected the top 10 scientific figures of the year, and Mojsov's name and story were among the highlights, acknowledging that his early groundbreaking research paved the way for the success of Wegovy, Ozempic, and other GLP-1 drugs [22]. Major media outlets have also begun to report on her once-unknown but extremely important scientific achievements.
Awards followed, with the VinFuture Award in 2023, the Princess of Asturias Award this year, and the Don Prize in Biotechnology and Medicine, and the academic community finally gave Mojsov recognition that was nearly 30 years late. This year's most important Lasker Clinical Medical Research Award was also awarded to these three veteran scientists in the field of GLP-1, which is not only well-deserved for Mojsov, but also encourages all scientists who are working silently in the field of basic scientific research, and each of them will be rewarded for their contributions and efforts.
Acknowledgments: We would like to thank Dr. Yixun Xu of Aspen Neuroscience in United States for reviewing and revising this article.
Original:
https://www.science.org/content/article/her-work-paved-way-blockbuster-obesity-drugs-now-she-s-fighting-recognition
Related information
[1] https://laskerfoundationorg/winners/glp-1-based-therapy-for-obesity/
[2] https://en.wikipedia.org/wiki/Joel_Habener
[3] https://en.wikipedia.org/wiki/Lotte_Bjerre_Knudsen
[4] https://www.pnas.org/doi/abs/10.1073/pnas.79.2.345
[5] https://onlinelibrary.wiley.com/doi/10.1111/j.1399-3011.1992.tb00309.x
[6] https://www.sciencedirect.com/science/article/pii/S0021925818673247
[7] https://www.pnas.org/doi/abs/10.1073/pnas.84.10.3434
[8] https://www.jci.org/articles/view/112855
[9] https://diabetesjournals.org/care/article/15/2/270/17386/Insulinotropic-Action-of-Glucagonlike-Peptide-I-7
[10] https://www.jci.org/articles/view/116186
[11] https://www.jci.org/articles/view/990
[12] https://www.nature.com/articles/379069a0
[13] https://www.nia.nih.gov/news/exendin-4-lizard-laboratory-and-beyond
[14] https://rs.yiigle.com/CN311282200901/205195.htm
[15] https://www.mdpi.com/1422-0067/24/13/10449
[16] https://www.163.com/dy/article/I2U88IGO0511CTRH.html
[17] https://www.nejm.org/doi/full/10.1056/NEJMoa2032183
[18] https://36kr.com/p/2508251857092868
[19] https://www.harringtondiscovery.org/news-media/2017/03/14/harrington-discovery-institute-announces-2017-harrington-prize-winners
[20] https://www.eurekalert.org/news-releases/475888?adobe_mc=MCMID%3D50617636419233758663203032174279153502%7CMCORGID%3D242B6472541199F70A4C98A6%2540AdobeOrg%7CTS%3D1727132441
[21] https://www.science.org/content/article/her-work-paved-way-blockbuster-obesity-drugs-now-she-s-fighting-recognition
[22] https://www.nature.com/articles/d41586-023-03927-1
Special Reminder
1. Enter the "Boutique Column" at the bottom menu of the "Huipu" WeChat official account to view a series of popular science articles on different themes.
2. "Back to Park" provides the function of searching for articles by month. Follow the official account and reply to the four-digit year + month, such as "1903", to get the article index in March 2019, and so on.
Copyright Notice: Personal forwarding is welcome, and any form of media or institutions may not be reproduced and excerpted without authorization. For reprint authorization, please contact the background in the "Huipu" WeChat public account.