Text: Zhang Qingdan, reporter of China Science News
"Accepting failure is a necessary quality for doing scientific research!" When Shao Sida was doing this new drug research on regenerative medicine, 90% of them failed, and he was almost crushed by one after another failures.
The love for stem cell research and the original intention to develop drugs that truly benefit human health have inspired Shao Sida to regain the motivation and determination to climb the mountains in one trough after another. In this tug-of-war, it took him 8 years to finally usher in the dawn and develop a lung-targeted drug-like small molecule that can stimulate the growth of lung stem cells.
He recently published the findings in the Proceedings of the National Academy of Sciences (PNAS) as first author and co-corresponding author. The study proposes that the body's regenerative function can be activated by drug stimulation to repair damaged lung tissue. The drug they developed will enter phase I clinical trials this summer and is expected to provide a new treatment option for serious lung diseases.
Shao Sida, who has always been concerned about the development of the field of stem cells in mainland China, wants to contribute his own strength. After studying abroad for 10 years, he resolutely returned to China to join the School of Science of Westlake University, established his own laboratory, and continued to explore more possibilities in the field of stem cell and tissue regeneration research with a young team of 8 people.
Shaw Star
Spraying a drug actually regenerates lung tissue
In recent years, there has been an increasing incidence of lung disease, and for many degenerative lung diseases, such as idiopathic pulmonary fibrosis (IPF), a key problem is the insufficient supply of stem cells to repair and reverse the damage. These cells are responsible for regenerating and promoting the growth of healthy tissue. Without them, pulmonary fibrosis will continue to worsen and lung function will continue to decline, eventually leading to respiratory failure.
However, there are currently no available treatment options for regenerating damaged lung tissue.
Most drugs work by slowing the progression of the disease. "The idea is to make drugs that control cell fate to stop or reverse the disease process. Peter G. Schultz, member of the National Academy of Sciences and director of the Scripps Research Institute, said. He is the co-corresponding author of the paper.
"We realized that chemical molecules may have more potential in this process, so we wanted to find a class of molecules to regulate the regeneration of alveolar stem cells and enhance their regenerative ability. Shao Sida said in an interview with China Science News.
To understand whether existing drug mechanisms can promote the growth of alveolar stem cells, the research team screened tens of thousands of bioactive molecules from a drug repurposing library established by the Scripps Research Institute's Clinical Translational Division.
Eventually, they set their sights on dipeptidyl peptidase IV. (DPP-4) inhibitors, which are often used as drugs for type 2 diabetes to control blood sugar. In experiments, the researchers found that the inhibitor can accelerate the growth of type II alveolar epithelial cells (AT2 cells).
However, new difficulties followed. "We found that the dose of DPP-4 inhibitors for the treatment of diabetes cannot work in the human lungs at all, and if it is to work, at least 5~10 times the dose is used. The doses required for lung repair with existing inhibitors are too high and unsafe for humans. Shao Sida said.
The initial plan based on the new use of old drugs has failed, is this project going to be sentenced to "death"?
After some struggles, Shaw sat down with his mentor Peter G. Schultz and his team members in drug development to discuss how to solve the problem. After a long debate and discussion, they finally settled on a new protocol – to design an inhaled drug formulation that could deliver targeted drugs directly into the alveoli.
"This can greatly improve the efficacy. Because oral drugs need to cross multiple layers of barriers to reach the location of action of alveolar stem cells, their effective concentrations will decrease layer by layer. Shao Sida said.
With this protocol in place, the research team tried and repeatedly engineered the structure of the DPP-4 inhibitor to achieve alveolar action through inhalation. After designing hundreds of molecular structures, a drug structure with a very good safety profile was finally obtained, CMR316. CMR316 can be delivered directly to the lungs through a nebulizer and has shown good results in various disease models as well as on lung samples from IPF patients, and is immediately degraded in the bloodstream after leaving the lungs, with no impact on human health.
As CMR316 is about to enter clinical trials, the research team is also developing compounds with new mechanisms to help regenerate heart cells and repair damage caused by heart failure, as well as small molecule drugs to replenish cells in organs such as the cornea, kidneys, and colon for the benefit of humanity.
From "love at first sight" to "love for life"
In 1990, Shao Sida was born in an ordinary family in Tianjin. He has always had good grades, and in 2009, he was admitted to the School of Life Sciences of Peking University with excellent results.
In his sophomore year, a class by Professor Deng Hongkui, a famous stem cell biologist in mainland China, made Shao Sida "fall in love at first sight" with stem cells.
"Stem cells are really cool! For example, embryonic stem cells can proliferate, differentiate, and grow into an organ or tissue. In addition, stem cells are present in the bone marrow, skin, intestines, and other parts. When we are sick, after the cells in the organs die, the stem cells can quickly start the regeneration process to repair the damaged tissue. Stem cells are like a 'restorative' on standby, protecting our body at all times. ”
"If some cells on a person's skin are taken out and planted in a special vessel, and it becomes the person's own stem cells through experimental operations, and then this stem cell is re-implanted into the mother's womb, the regenerated individual will be exactly the same as this person......" In the class, Shao Sida was immersed in his imagination, and the scenes in science fiction seemed to be realized in the laboratory, and he was extremely excited.
His interest in stem cell research was instantly ignited! He actively joined Deng Hongkui's lab, and in those two years, his passion for stem cells continued unabated.
Moreover, Sida Shao is very fond of chemistry. He wants to continue his research on stem cells with some chemical means. After graduating from Peking University in 2013, he applied to study for a Ph.D. in the team of Professor Schultz at the Scripps Research Institute in order to fulfill his scientific research aspirations.
The Scripps Research Institute has an excellent academic reputation and is well known in organic chemistry and chemical biology. Shao Sida is engaged in chemical biology. His supervisor, Professor Schultz, is a pioneer in chemical biology and a leading figure in academia and industry, and is the founder of several high-tech and biotechnology companies.
Due to his background in biology during his undergraduate years, Shao Sida, who knew nothing about chemistry, had a very difficult time in the first few years, and he often forgot to sleep and eat, buried deep in the sea of books, and worked hard to digest every new set of theories. Moreover, Professor Schultz's laboratory is very large, and the equipment and equipment in it have to be tried and explored by himself little by little.
Later, as the shortcomings of chemistry were filled, the topics done by Shao Sida also improved. At that time, he had a "soft spot" for stem cells, and he started research on alveolar stem cell regeneration.
In order to continue his research, he chose to stay in the clinical translational department of the Scripps Research Institute as a researcher, continue to deepen the clinical translational research of alveolar stem cell regeneration, and strive to develop his research results into new drugs.
"A study is like my own child, raising a child hopes that he can thrive, learn hard, and make a difference in the future, and I also hope that the molecules I have discovered can be continuously optimized in my hands, and continue to explore its potential and value. If you give it to someone else to do it, it's like handing over the child to your stepfather and stepmother, and it feels very uncomfortable. Shao Sida feels that even if it is not successful, at least it will draw an end to his scientific research journey.
With the unremitting perseverance of him and his team members, this 8-year study has delivered a satisfactory answer. In August 2023, Sida Shao returned to China to join the School of Science of Westlake University full-time as a distinguished researcher, continuing to engage in research in the direction of stem cell and tissue regeneration. "In this life, I have been rooted in the field of stem cells!"
Influenced by two teachers, he devoted himself to education
Shao Sida's attitude, thinking and philosophy towards scientific research are deeply influenced by the two mentors.
As a leader in the field of stem cell research in mainland China, Deng Hongkui has long thought of using small molecule methods to solve the stem cell problem. This was something that almost no one dared to think of at the time. Because the language of cells is genes and proteins, and chemical molecules are more like another language, like adding a foreigner to a group of Chinese.
At that time, the small molecule method was simply a fantasy. However, Deng Hongkui's laboratory invested a lot of manpower and material resources, braved difficulties, and took several years to successfully tackle key problems, and realized the use of small molecules to prepare somatic cells into pluripotent stem cells.
"Mr. Deng taught me to aim for important scientific problems, not to be afraid of difficult problems, not to be afraid of failure, and to have a high standard for myself. He was a man of great integrity and purity, which is something I can learn from. Shao Sida said.
Shao Sida, who usually has a big personality and is very cheerful, also experienced a beating of failure during his doctoral studies. "At that time, when I was experimenting, when someone else succeeded, and I couldn't, the pressure would increase dramatically. 90% of the time it was a failure, and there were a few times when I was crying in the lab, and the misfortune almost broke me. ”
The training of scientific research is actually a training on how to face failure, and accepting failure is a necessary quality for doing scientific research. Shaw said that in the face of many difficulties, his mentor, Professor Schultz, set a good example.
For Professor Schultz, the success of the day was not just about whether the experiment could be done. As the director and founder of the company, he should be concerned about the development of the institute, and many times, he may hit a wall in many things. "When I met him on the day our article was rejected by other magazines, he said to me: 'Today, since the morning, one bad thing after another, and it's getting worse and worse. In Shao Sida's view, "the higher a person's position, the more troubles he has, but he can still maintain his enthusiasm and enthusiasm for life and work." ”
"We all have to learn to be positive and optimistic, and learn to absorb the things that don't go well. There are many blows, and only perseverance can support you to climb over the hills and ravines and persevere until the moment when the willows and flowers are bright. ”
After ten years of "polishing" abroad, Shao Sida's scientific research ability has been greatly improved. After getting married and having children in the United States and having a happy family, he still chose to return to China for two main reasons: first, the domestic scientific research strength has advanced by leaps and bounds in recent years, and there are many opportunities for scientific research and development.
At present, there are 8 members of Shao Sida's team, including doctoral students and postdoctoral fellows. Deeply influenced by the two mentors, Shao Sida attaches great importance to the training of students' thinking patterns. He often shares his thoughts with his students, and also guides them to look at scientific problems from a high vantage point. "I hope that they will be able to form an open mindset and cultivate a holistic view of science while deepening their own research fields. ”
Shaw Star's team
When taking students, Shao Sida put a lot of effort into it, and he would take students to do experiments by hand. "We are a young research group, and while I have the energy right now, I want to teach every student well. If you are interested in chemical biology and stem cell biology, please feel free to contact me if you are also interested in using chemical molecules to deconstruct the tissue regeneration process. ”
And Shao Sida is very discouraged, and he is still engaged in research in the middle of the night. "I'm used to coming early and leaving early, arriving at six or seven o'clock in the morning and going home at seven or eight o'clock in the evening, and I often tell my students not to do experiments until one or two o'clock in the evening. They are just like my children, no parent would like their children to hurt their bodies by staying up late. ”
Reference Links:
https://doi.org/10.1073/pnas.2400077121
*Image provided by the interviewee