After making groundbreaking contributions, she was "rescued" by the 2024 Lasker Award

Among the three winners of the 2024 Lasker Clinical Medical Research Award, Svetlana Mojsov, a scientist at Rockefeller University, is undoubtedly the least visible. Although she participated in the initial pioneering research on GLP-1 and deciphered the true GLP-1 activity, she was able to quickly and accurately synthesize experimental materials in large quantities, gaining an advantage in the fierce competition. However, in the following 30 years, she disappeared into obscurity: GLP-1 drugs became popular and won many awards, but her name was not among the winners; now in her early 70s, she is still an associate professor of research. It was not until a year ago that her legendary past was reported by the media.

Compiled by Xiaoye

In June this year, Svetlana Mojsov was returning to New York with her husband after her vacation. Because her flight was delayed, she took the time to check her email and saw an email from Joe Goldstein, the 1985 Nobel Prize winner in Physiology or Medicine and the current chairman of the Lasker Medical Selection Committee.

Goldstein's email brought good news: Mojsov became one of the three winners of the 2024 Lasker Award for Clinical Medical Research. They were awarded for discovering and developing GLP-1 drugs, which completely changed the treatment strategy for obesity[1]. The Lasker Award is one of the most important awards in the global biomedical field and is also known as the "Nobel Prize weathervane." In the past 20 years alone, a total of 32 Lasker Award winners have subsequently won the Nobel Prize. In addition, due to the great contribution of GLP-1 drugs to the treatment of diabetes and obesity, people are increasingly speculating that they may win the Nobel Prize.

In fact, just one year ago, Mojsov's outstanding academic contributions were little known even in the scientific research community. It was not until Science, Nature and some media reported on her that her legendary scientific research story became public.

Svetlana Mojsov, Research Associate Professor | Source: Rockefeller University website

The forgotten pioneering contribution

The other two scientists who won the award together with Mojsov are Joel Habener, an endocrinologist at Massachusetts General Hospital (MGH) in the United States, and Lotte Bjerre Knudsen, a Danish scientist at the multinational pharmaceutical company Novo Nordisk. Habener has been a leader in the field of GLP-1 research since the 1980s and has won numerous awards[2] and is well-known. Knudsen is the chief scientific advisor of Novo Nordisk and has led his team to "break new ground" in the field of diabetes and obesity drug research and development since the 1990s[3].

Compared with them, Mojsov remained unknown in various scientific narratives related to GLP-1, diabetes and obesity for nearly 30 years. It was not until 2023 that she bravely spoke for herself and finally won public recognition from the academic community.

Back in the 1970s, Mojsov, who is from the former Yugoslavia, entered Rockefeller University to pursue graduate studies in the laboratory of the famous chemist Bruce Merrifeld. She specialized in glucagon, a hormone released by the pancreas that can be used to detect insulin: insulin can lower blood sugar, while glucagon can raise blood sugar. Therefore, scientists believe that inhibiting glucagon may help treat type 2 diabetes. At that time, the Merrifield laboratory proposed a pioneering method for synthesizing glucagon, and Mojsov mastered the synthesis technology. She stayed in the laboratory as a postdoctoral fellow to improve her technology.

While still a graduate student, Mojsov met her future husband, Michel Nussenzweig, a renowned immunologist at the time. He often invited Mojsov to tea to help her relieve the pressure of writing papers. In the early 1980s, Nussenzweig obtained his residency at MGH, and Mojsov joined the hospital's endocrinology department as an instructor. She was also in charge of a new department to synthesize peptides for scientists in the department. As long as a certain amount of peptides were synthesized on demand every day, this work did not take too much time for Mojsov. So she had the opportunity to carry out personal research work, and she already had a clear goal in mind: the mysterious peptide called glucagon-like peptide-1 (GLP-1).

Also in the 1970s, Habener was already a rising star in the field of endocrinology. His team had been studying key hormones in the pancreas of anglerfish, including glucagon, and they froze the islet cells that produced the hormones and eventually cloned proglucagon.

In 1982, the team published a paper[4] reporting that the fish gene encodes a large precursor protein that is cut and processed to form glucagon. There is also an amino acid fragment embedded in proglucagon that is similar to glucagon. This is the famous GLP-1. In addition, the amino acid sequence of GLP-1 shares certain features with incretin (GIP), which was the only known member of the legendary incretins at the time. Scientists believed that incretins had the potential to treat type 2 diabetes, but experimental results showed that using it did not effectively affect the insulin levels of diabetic patients.

So, both Habener and Mojsov wanted to know if GLP-1 was different. The first question to be answered was where in the body the peptide’s activity was generated. In her small office, Mojsov carefully observed the 37-amino acid chain in the mammalian GLP-1 sequence. Based on its similar properties to glucagon, she boldly hypothesized that the 31-amino acid chain from position 7 to position 37 in the large GLP-1 peptide might be an incretin. So, on a piece of paper with the amino acid sequence of proglucagon printed on it (see the figure below), she wrote down the function of GLP-1 and was determined to prove her hypothesis [5].

This handwritten paper describing the function of GLP-1 was used in a paper Mojsov published in the International Journal of Peptide and Protein Research in 1992.

To find the 7-37 amino acid fragment in the intestine, Mojsov needs fish with antibodies, because the peptide itself may exist in extremely small doses and is difficult to detect, and the antibody can more clearly mark the location of the peptide. She first produced GLP-1 in large quantities and stored it in glass bottles; then injected different fragments of the peptide into the experimental rabbits, waited for two months, and let the antibodies proliferate as much as possible in the rabbits' blood; finally, she collected blood samples from the rabbits' carotid arteries and separated the antibodies. All of this was done independently by Mojsov, and her years of laboratory work experience made her operate with ease.

Downstairs in Mojsov's office, Habener's team began exploring the biology of GLP-1. In 1984, the lab recruited postdoctoral researcher Daniel Drucker, whose job was to determine which cell types could produce such a peptide. As a novice endocrinologist with no laboratory experience, Drucker quickly ran into trouble because no one could assist or guide his work.

Although Habener and Mojsov conducted independent research, Habener obviously knew what Mojsov was doing. So, at Habener's suggestion, Drucker found Mojsov and talked about cooperation. At this time, Mojsov said that he had produced antibodies against different GLP-1 fragments and had a set of methods to detect the presence of GLP-1 fragments. Next, Mojsov teamed up with some researchers in Habener's laboratory to use Mojsov's method to track different GLP-1 peptide fragments in various tissues of mice. Despite this, Mojsov still worked alone most of the time. In the end, she discovered the active GLP-1 (7-37) amino acid chain in the mouse intestine.

In 1986, Mojsov and Habener published a paper together[6], which described in detail the presence of the GLP-1 (7-37) amino acid chain in the intestine. Today, this paper is recognized as an important milestone in the development of this field, with Mojsov's name listed first and Habener as the corresponding author, listed last.

Then, the second question followed: Is the 7-37 amino acid chain of GLP-1 in the intestine biologically active? Specifically, can it trigger the pancreas to release insulin? Using Mojsov's synthetic GLP-1, a study led by Drucker demonstrated[7] that GLP-1 can indeed promote insulin secretion in rat pancreatic islet cell lineages. Next, Habener wanted to further test the effects of GLP-1 on the entire organ, so he contacted his friend, endocrinologist Gordon Weir. The latter developed a rat pancreas model that lived in an acrylic incubator filled with oxygen, and the researchers measured the model animal's insulin levels every minute at room temperature. When Weir injected Mojsov's synthetic GLP-1, he found that the amount of insulin output increased. Subsequently, even if the amount of peptide injected was reduced, even if the injection was extremely small, the researchers unexpectedly observed the same effect.

Mojsov measured the intake of GLP-1 and confirmed that the peptide and insulin responses were consistent. The two hormones "run side by side and increase at the same time." She described it as "a wonderful experiment." Finally, the paper was published in The Journal of Clinical Investigation in 1987 [8], with only three authors, Mojsov's name was still listed first, and Habener was still at the end. Weir commented that this paper was the most important research he had assisted in.

After a series of animal model studies, Habener's team continued to move towards the human testing stage. They collaborated with Mojsov and David Nathan, a diabetes expert at MGH[9]. Nathan injected the peptide into healthy subjects and diabetic patients and found that GLP-1 promoted the release of insulin when blood sugar levels rose. This study was published in the journal Diabetes Care in 1992, which can be said to be the last GLP-1 collaborative study that Mojsov participated in.

GLP-1 drugs gradually become "gods"

Since the 1990s, Mojsov's research career has taken a turn. Her husband Nussenzweig received a job offer from Rockefeller University with an attractive salary, and he readily accepted it. So Mojsov returned to New York with her husband, and started a new chapter in her life with hope.

Her involvement in the development of GLP-1 drugs ended there. Since then, GLP-1-related research has advanced by leaps and bounds, ultimately providing a powerful new weapon in humanity's fight against disease.

At that time, in addition to the Habener team, research teams in other countries were also actively exploring the impact of this peptide on human health, and more and more studies were published: a study co-led by Jens Juul Holst, a professor of medical physiology at the University of Copenhagen in Denmark, and Michael Nauck, an endocrinologist currently at Ruhr-Universität Bochum in Germany [10], also found that GLP-1 can normalize blood sugar levels in patients with diabetes. In addition, the Holst team also conducted a survey on 20 healthy young men [11]. They received intravenous injections of GLP-1 after a hearty breakfast. At the buffet lunch time, the subjects ate less than the placebo control group. The team at Hammersmith Hospital in London, UK, also reached a similar conclusion [12]. Injecting GLP-1 into the brains of rats can strongly suppress the urge to eat, leading to loss of appetite. This also seems to suggest another application transformation direction of GLP-1 in the future.

The basic scientific research results that were continuously reported allowed pharmaceutical companies to first see the new potential of developing GLP-1 drugs to treat 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 its eventual becoming a drug that patients can safely treat.

In 2005, the first GLP-1 drug, Byetta, was approved for type 2 diabetes. However, the key ingredient is synthetic exendin-4, which is derived from exendin-4 found in the venom of the Gila monster. The structure and function of this peptide are similar to human GLP-1, and it will not degrade within hours after being injected into the body[13], thus producing a therapeutic effect.

Five years later, Novo Nordisk used the human body's 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 the United States. Liraglutide not only retains the various physiological properties of natural GLP-1, but also has a high and long-lasting blood sugar-lowering effect and is not easily degraded by degrading enzymes. In addition, its half-life is as long as 12 to 14 hours. For diabetic patients, only one subcutaneous injection per day is required to achieve a good blood sugar-lowering effect.

There are more Easter eggs to come. The application range of GLP-1 drugs is not limited to diabetes treatment. As mentioned above, GLP-1 has multiple effects on various organ systems, the most relevant of which is to reduce appetite and food intake, thereby achieving the purpose of weight loss. This is a very wonderful side effect discovered in clinical trials, which can be fully utilized to solve another public health crisis facing modern people: overweight or obesity.

Since the 1960s, there have been various short-term weight loss drugs such as phentermine, benzphetamine and diethylpropion, but there is no long-term safety data [15]. Until the 1990s, the weight loss drug "Fen-Phen" caused serious health problems such as fatal heart valve disease and pulmonary hypertension [16]. People still failed to find a safe and effective weight loss drug. Therefore, pharmaceutical companies have made 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 US Food and Drug Administration.

In 2022, its next-generation GLP-1 drug, semaglutide, continued to be approved for the treatment of diabetes (marketed as Ozempic) and weight management (marketed as Wegovy). It quickly became popular in the market. According to statistics, 1.7% of people in the United States were prescribed Ozempic or Wegovy in 2023. Unlike previous drugs, semaglutide only requires one injection per week. According to a study published in the New England Journal of Medicine [17], subjects taking semaglutide lost an unprecedented 15% of their body weight in about 16 months, but also reported common adverse reactions: 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, lixisenatide, dulaglutide, benaglutide, liraglutide, semaglutide, telpotide, etc. [18]. In the same year, GLP-1 drug therapy was successfully listed as one of the top ten scientific breakthroughs of the year by Science [13].

Some of the common GLP-1 agonist drugs on the market, source: medpagetoday.com

No more silence, finally recognized

Unlike the popularity of GLP-1 drugs, Mojsov's research career became dull after she left the relevant research and development field. She followed her husband to Rockefeller University and entered the laboratory of immunologist and future Nobel Prize winner Ralph Steinman as a research assistant professor. At that time, Mojsov also had a toddler and a baby to feed. Like many working women, she had to work harder and struggle to maintain a balance between raising children and expanding her career.

With funding from the National Science Foundation, she changed her subject and began studying fish GLP-1 biology, collaborating with scientists studying fish glucose metabolism. At the same time, she also provided help with peptide biology to other researchers in the lab, and she found that her collaboration with junior scientists brought her a different sense of accomplishment. She believes that science is a collaboration, and whether it is a young scientist who has just entered the scientific research community, a junior scientist, or a senior scientist, everyone makes valuable contributions to science. She does not agree that the so-called senior scientists are the biggest contributors to cutting-edge scientific knowledge, and junior scientists are just auxiliary.

Steinman's laboratory became Mojsov's stable scientific research position, and she stayed there for more than 20 years until Steinman passed away in 2011. Today, Mojsov still works at Rockefeller University as a research associate professor, but she does not lead a laboratory herself, but collaborates with different scientists.

Mojsov has always been proud of her basic research on GLP-1 at MGH and has always been concerned about related progress. In 1996, she learned from an employee of a biotechnology company that the patent for GLP-1 had been granted several years ago.

Soon, she found two patents registered in 1992, covering a "fragment" and "derivative" of GLP-1 that could boost insulin secretion. A third patent was also pending. However, all the patents listed Habener as the sole inventor, with no connection to Mojsov at all, which shocked her.

Mojsov decided to hire a law firm to help him fight for his co-inventor rights. After years of fighting with the MGH patent department, MGH finally agreed to amend four patents (including the fourth patent awarded to Habener alone in 2005) between 2004 and 2006 to list Mojsov as a co-inventor, and the United States Patent and Trademark Office officially confirmed the change of invention rights. The fifth patent was awarded directly to the two scientists in 2006.

Mojsov said MGH agreed to give her a third of the drug's royalties, with Habener getting the rest. She declined to say how much, but said: "For an academic, it's not bad, there's nothing to complain about."

Although Mojsov received due rewards for her pioneering contributions, her reputation was long buried.

The great success of GLP-1 drugs has brought the scientists who have worked hard behind the scenes into the public eye, and they have won various medical awards. In 2017, Habener, Drucker, and Holst jointly won the Harrington Prize for Innovation in Medicine in recognition of the three scientists' "discovery of incretin and its transformation into transformative new therapies"[19]. In 2020, they won the Warren Alpert Prize from Harvard Medical School[20]. In 2021, the internationally renowned biomedical research award, the Canada Gairdner Award, was also awarded to the three scientists[21].

The discovery of GLP-1 was mentioned in all the award-winning results, however, Mojsov's name did not appear in any list of related scientific awards, and her outstanding contribution was forgotten.

Jeffrey Flier, former dean of Harvard Medical School, admitted that scientific awards are an important way for academic recognition. Typically, award committees focus on scientists nominated by scientific research institutions and peers. If Mojsov did not hold an important position in the GLP-1 research process and did not have a lasting influence, then he would likely be at a disadvantage.

Even though Mojsov was absent from the translational research and development stage of GLP-1 for various reasons, it does not mean that all her efforts in the initial basic research stage can be wiped out. Drucker, now a professor at the University of Toronto, admits that Mojsov's important contribution should not be ignored. Habener also always remembers Mojsov as an important collaborator: "She participated in the initial pioneering research and deciphered the true activity of GLP-1. She was able to synthesize large quantities of peptides quickly and accurately, which gave us an advantage in the fierce competition."

In addition, Mojsov's obscurity over the past 30 years may be related to her personality. She is a very private person. Until last year, she hardly told anyone about her past participation in the GLP-1 research. After learning everything, her graduate school classmate, chemist George Barany (the two have maintained a friendship for nearly 50 years), Barany's brother, chemist Francis Barany, and some Rockefeller colleagues all supported her to speak out publicly. Francis Barany said: "Mojsov's experience is a cliché in the scientific community. There are no bad people here, but she has indeed not received the recognition she deserves."

Although it was not easy for Mojsov to talk about herself publicly, she finally stood up and tried to speak for herself. At the same time, Habener, Drucker and Holster all confirmed Mojsov's important contribution, and Habener expressed his support for Mojsov and stood on the same front with 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 scientists of the year, and Mojsov's name and story became a highlight of the article, acknowledging that her early pioneering research paved the way for the success of Wegovy, Ozempic and other GLP-1 drugs in the future [22]. Major media outlets also began to report on her once unknown but extremely important scientific achievements.

Awards followed, including the VinFuture Award in 2023, the Princess of Asturias Award this year, and the Tang Prize in Biotechnology and Medicine. The academic community finally recognized Mojsov nearly 30 years late. This year's most important Lasker Clinical Medical Research Award was also awarded to these three veteran scientists in the GLP-1 field. For Mojsov, it is not only well-deserved, but also an encouragement to all scientists who are quietly working in the field of basic scientific research. Everyone's contribution and hard work will eventually be rewarded.

Acknowledgements: We would like to thank Dr. Yixun Xu of Aspen Neuroscience for reviewing and revising this article.

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