After Zhang Lin excitedly left the laboratory, Yang Ping turned his attention back to the "identity profile" on the big screen.
Even if this is indeed a common target for pancreatic cancer, designing a K factor that can accurately recognize it is extrely difficult, not to ntion ensuring the safety, specificity, and delivery efficiency of the new K factor..."
Yang Ping analyzed: "Currently, we face several technical challenges — the resolution of the three-dinsional structure of protein complexes; designing K factors with high affinity and specificity based on this structure; the stability and delivery system of the K factor in vivo. Designing the K factor is the hardest part. Even though we have the existing K factors as references, it is still a highly challenging task."
If the professor says it’s difficult, then it’s really difficult.
"I can take on the structural analysis." Lu Xiaolu volunteered, "Didn’t our institute just install the cryo-electron microscope, a 300kV Titan Krios, equipped with the latest direct electron detector? If the sample preparation is good, we can theoretically resolve down to near atomic resolution."
"How much sample is needed?" Song Zimo asked.
"Purified protein complex, at least 0.5 milligrams, with a purity of over 95%." Lu Xiaolu stated the numbers.
Tang Shun took a deep breath: "Purify 0.5 milligrams of mbrane protein complex from pancreatic cancer cells? How many cells would we need to culture?"
"At least... a 500-liter culture scale." Xu Zhiliang quickly calculated, "And... mbrane protein purification yields are usually less than 1%, so... in actuality, even more is needed."
"At regular speed, this would take at least two months, but using our amplification technology can speed up the culturing process. Bring your sample cells to , I’ll handle the culturing; culturing cells is our expertise." Tang Shun took on the task of culturing cells.
"Maybe there’s another approach to save ti and start observations imdiately." Griffin, who had been silent all along, suddenly spoke, his Chinese was fluent.
Everyone turned to look at him.
Griffin walked to the whiteboard and picked up a pen: "During my ti in the United States, I participated in a non-traditional structural resolution project. We were dealing with an extrely difficult-to-purify mbrane receptor and eventually adopted an in situ structural resolution thod, not purifying proteins, but directly observing in its near-natural state on the cell mbrane."
He drew a simple diagram: "Specifically, we labeled the target protein with gold nanoparticles and used cryo-electron tomography technology to conduct three-dinsional imaging of the local regions of intact cells. Although the resolution doesn’t reach the atomic level, it’s sufficient to discern the general conformation and key interaction interfaces of the protein. With this information, atomic details can be completed using computational modeling."
"Has this thod been used before?" Song Zimo asked.
"In 2019, there was a paper in Nature that resolved the in situ structure of the NMDA receptor in synapses with a resolution of 4.5 Ångströms." Yang Ping accurately cited, "The key lies in the labeling technology and image processing algorithm. Gold labeling might interfere with the protein’s natural conformation, but now we have better options—gene-encoded mini-tags, like ALFA-tag or SpyTag, which can covalently bind to specific nano-labels, causing less interference."
Griffin did not expect Professor Yang to be knowledgeable about such niche papers; his breadth of knowledge was impressive.
Lu Xiaolu’s eyes lit up: "If we can see the structure of this identity lock in situ in cancer cells, it can not only guide K factor design but also verify its state in the real tumor microenvironnt, which is more aningful than potentially denatured proteins after purification."
"But the technical difficulty is high." Griffin cautiously said, "Cryo-electron tomography has extrely high demands on sample preparation, low signal-to-noise ratio in images, and complex data processing..."
"We can give it a try." Yang Ping decided, "Lu Xiaolu, you’re responsible for this direction, keep communicating with Griffin, and start exploring conditions from a small number of cells."
"Yes, Professor." Lu Xiaolu nodded seriously.
Griffin was very excited that his idea was recognized by Professor Yang, marking a highlight in his academic career worth bragging about.
After arranging the structural analysis work, Yang Ping turned to another challenge: "Even with the structure, designing a K factor is still a challenge. Traditional antibodies or small molecules hardly et the requirents, as antibodies are too large and difficult to penetrate the tumor matrix, while small molecules lack specificity and easily miss targets."
"Perhaps we can take inspiration from nature." Song Zimo pondered, "Professor, do you rember the molecular adhesive concept you ntioned before? So natural compounds can bring together two proteins that don’t naturally bind. If we can find or design a molecule that specifically binds the identity lock of pancreatic cancer cells to the killing receptor of immunocytes..."
Yang Ping thought for a mont: "K factors are entirely different in theory from these matters. Before K Therapy was widespread, weren’t we always searching for new K factors? We found nothing! Now that we’ve identified the identity lock for pancreatic cancer, based on our research results from osteosarcoma, this identity lock must correspond to a key. This key must exist; we just haven’t found it yet. I will handle this part of the work."
The professor is personally taking charge?
The research process of the vaccine enhancer X-2 is still vivid in mory; the professor, along with a few newly graduated doctors, overca nurous difficulties to let X-2 shine brightly.
Now the professor is personally researching a K factor for pancreatic cancer? Does that an it’s already halfway to success? Song Zimo’s intuition suggested so.
...
At eleven o’clock at night, most of the lights in the laboratory building of the institute had gone out, except for the lights still on in the structural biology laboratory.
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