godfather of surgery

Chapter 1306 Clan

"Professor, I will treat this research as a long-term project. Do you think that's appropriate?" Zhang Lin was excited about the breakthrough he had made in his research.

Yang Ping encouraged him: "As long as you believe it is correct, and you do not engage in fraud, and you conduct research in a down-to-earth manner, it is not a problem even if you do not get results in the end."

After leaving Zhang Lin's laboratory, Yang Ping returned to his office to rest.

The electronic screens displayed different data: on the left was the latest in-situ high-resolution structure of the pancreatic cancer PANC-ID1 complex on the cell membrane, as analyzed by Lu Xiaolu's team; in the middle was a cryo-electron tomography image of a PAC-FUS1 fusion protein tumor provided by Katherine Miller; and on the right was a three-dimensional prediction model of osteosarcoma-specific surface antigens, which had just been sent from the orthopedic tumor research laboratory.

Yang Ping had been sitting in front of these three sets of data for four hours.

The teacup had long since gone cold, but he was completely unaware. His fingers slowly slid across the touchpad, rotating, enlarging, and overlaying the three structural diagrams.

Over the past few months, the global rollout of K therapy has proceeded as planned, and vaccine enhancer technology has quietly garnered patent fees from various multinational pharmaceutical groups. Yang Ping's current focus is entirely on the essence of cancer cell identity locking.

Why is PANC-ID1 a common marker for most pancreatic cancers?
Why did the PAC-FUS1 fusion protein replace PANC-ID1 as another identifier for pancreatic cancer?
Why is there a protein complex with the same high specificity on the surface of osteosarcoma?
These questions haunted him like ghosts deep within his mind.

It's about four o'clock in the afternoon.

Yang Ping suddenly did something strange: he turned off all color rendering and converted all three structural models into pure gray electron density cloud maps, removing the visual interference of color and leaving only the most essential shapes.

He then adjusted the three models to approximately the same size and arranged them side by side.

He held his breath at that moment.

Despite low sequence homology, different constituent subunits, and different locations on the cell membrane, the core regions of the three structures exhibit a striking topological similarity.

It is a multi-layered, asymmetric helical-loop-helical superposition structure, like an ancient combination lock, with a core of a highly ordered pocket or groove formed by hydrophobic amino acids. Among the three, the shape of this core region, the charge distribution pattern, and even the spatial arrangement of certain key hydrogen bond donors/acceptors share undeniable commonalities.

Yang Ping quickly retrieved the biochemical properties data of the three molecules. The core pocket of PANC-ID1 has been shown to bind to specific endogenous lipid molecules; this binding slightly alters the complex conformation, affecting downstream signaling. Although the core region of PAC-FUS1 incorporates an exogenous sequence, molecular dynamics simulations show that it retains its ability to bind similar lipid molecules, albeit with altered affinity. Furthermore, in the predictive model for osteosarcoma targets, the corresponding region also exhibits highly hydrophobic characteristics.

“It’s not a coincidence…” Yang Ping muttered to himself, his fingers trembling slightly.

He casually pulled out a sheet of A4 paper and started writing and drawing on it with a pencil.

Tumor identity-locked phylogenetic hypothesis:
The surface antigen complexes of PANC-ID1 (pancreatic cancer), PAC-FUS1 variants (specific pancreatic cancer subtypes), and OS-ID1 (osteosarcoma) share a unique "topological folding pattern" in their tertiary/quaternary structures, with an evolutionarily conserved hydrophobic binding pocket at the center.

These three seemingly different tumor surface markers may belong to the same functional superfamily. They are not entirely independent inventions, but rather based on an ancient cell surface recognition module, possibly originating from embryonic development, tissue repair, or cell communication, which is abnormally recruited, modified, or fixed in expression during tumorigenesis.

The core function of this module may not be carcinogenicity itself, but rather providing an identity authentication interface. Under normal physiological conditions, it may participate in limited, tightly regulated intercellular recognition, such as specific stem cell niches and tissue boundary maintenance. Cancer cells hijack this interface, turning it into an identity lock for maintaining their own survival community or evading immune surveillance.

If such an "identity lock" is a family, then theoretically, there should be a corresponding "key" family, the K-factor series. The K-factor and its corresponding target previously discovered in osteosarcoma constitute a perfect key-lock combination.

If we assume that these identity locks are a family series, then the K-factor should also have a family series. If we can decipher the inherent patterns of these series, we can reverse-engineer the K-factor to unlock the lock.

Different tumor types, and even different subtypes of the same tumor, may use different structural variants within the same family lineage as locks. The key to current research lies in mapping the complete family tree of these "locks" and finding or designing the "keys" that can open specific locks.

After writing this, Yang Ping leaned back in his chair and closed his eyes. The image in his mind became even clearer: not a target, not a therapy, but a complete, hidden identification system, a language of identity hidden by cancer cells, a complete, undiscovered theory.

This is no longer as simple as discovering a new target; it's an attempt to decipher a completely new mechanism of cancer.

Song Ziming, Tang Shun, and Lu Xiaolu knocked on the door for a long time, but Yang Ping did not respond. When Yang Ping came out of his thoughts and remembered the faint knocking sound, he opened the office door.

Everyone breathed a sigh of relief when they saw that Yang Ping was safe and sound. They knew that the professor often closed his eyes to rest and immerse himself in thought, but sometimes they couldn't help but worry.

“I need high-resolution structural data of surface antigen complexes from all available types of solid tumors, especially those that are tumor type specific,” Yang Ping blurted out.

Song Ziming was taken aback: "Professor, you mean all types? The amount of data and the workload of alignment analysis..."

“I know, it’s enormous,” Yang Ping interrupted him, pushing his A4 paper draft in front of Song Ziming. “But I suspect we’ve hit the boundary of something, not a point, but a surface, or even a system.”

The office fell silent. Tang Shun stared at the A4 paper, his breathing quickening. He knew better than anyone what it meant if this similarity in topology was true and universal.

Moreover, all three understood what it meant each time the professor produced an A4-sized draft.

“This…this is like discovering a ‘dark matter family’ in the world of protein structures,” Lu Xiaolu murmured. “The surface sequences vary greatly, but the core folds and functional pockets are preserved. If we don’t look at them together and in this way, we would never be able to find them.”

“So we need more evidence.” Yang Ping turned to Song Ziming. “Contact all the hospitals and research institutions we can reach around the world, especially those with unique tumor cell lines or organoid banks, and ask them to provide surface proteomics data and as much structural information as possible.”

“I’ll contact Dr. Catherine at Anderson right away?” Griffin said.

“Her PAC-FUS1 sample is extremely important. We need more, we need many more other samples—all the samples I just mentioned, the more the better. One Anderson is far from enough; we need more supporters.” Yang Ping’s tone was calm but undeniable. Dr. Griffin immediately asked, “Professor, from a clinical perspective, if this ‘pedigree’ hypothesis holds true, what will it change?”

Yang Ping turned around and drew a large tree-like diagram on the whiteboard: "Imagine this is an evolutionary tree of tumor identity locks. The root of the tree may be that ancient cell recognition module. Different branches of the trunk represent different major tumor categories, such as epithelial origin and mesenchymal origin. More detailed branches represent subtypes, and even variations in individual patients."

He pointed to different parts of the tree: “Traditional targeted therapy is like trying to cut off a small branch, such as an EGFR mutation, but the tree will sprout from other places. Immune checkpoint inhibitors are like spraying weeds on the whole tree, but they may damage the soil—the autoimmune system, while our K therapy…”

He paused, circling several key branches of the tree: "If the K-factor is the key, then theoretically, each specific key can open the lock on the corresponding branch. But if we can understand the construction principles, evolutionary laws, and core weaknesses of the entire locking system..."

He forcefully crossed out the trunk and several key connection points of the tree: "We might be able to design a master key that can destroy the connection points of the trunk, or a jamming code that can induce the entire identification system to collapse. Then we will no longer be able to defeat them one by one, but shake their foundation. Even if we can't do that, we can use a bunch of keys to unlock all the branches."

The laboratory was silent; the target was too big, almost frighteningly so.

Next, the laboratory entered an unprecedented high-speed operating mode, and the influence of the Sanbo Institute was astonishing. A flood of data poured in from all over the world: novel conformations of the HER2-related complex in breast cancer, specific membrane protein clusters in glioblastoma, unique glycosylated surface antigen structures in colon cancer…

The research team developed a new structural alignment algorithm using cryo-electron microscopy and supercomputing resources, which can ignore sequence differences and directly search for topological similarities. The results are astonishing: among more than sixty solid tumor surface marker structures with clear type specificity, more than 70% showed varying degrees of similarity to the PANC-ID1 core folds! The highest similarity was concentrated in tumors with similar developmental origins, but even between tumors with very different origins, subtle, yet far from accidental, structural echoes were found.

More importantly, in several cases, they discovered a correlation between these "locks" and tumor malignancy and metastatic tendency. A certain conformational variant of the "lock" appears to be directly related to cancer cells acquiring invasive capabilities, resisting apoptosis, or shaping an immunosuppressive microenvironment.

Yang Ping is spending increasingly more time locked in his office. He wants to take advantage of the immediacy and vast amount of time that the system space laboratory provides to conduct a comprehensive study of certain hidden patterns in these tumor cells.

Gradually, the whiteboard was filled with complex phylogenetic diagrams, structural evolution paths, and hypothetical "key-lock" interaction models.

He is extracting a clear logical chain from massive, chaotic structural biology data.

The number of A4-sized drafts on my desk is also increasing.

Just a few days later, when he returned to the team, the whiteboard behind him was covered with symbols and arrows, which looked like gibberish to outsiders.

“The chain of evidence is theoretically closed.” Yang Ping’s voice was a little hoarse, but it carried immense weight. “What we have discovered is not a family, but a kingdom—I call the ‘Tumor Identity Module (TIM) superfamily’.”

He pointed to the core area of ​​the whiteboard: "The core of TIM is a structural module that appeared early in evolution and is used for cell-specific recognition. In normal adult tissues, most of its members are silent or expressed at very low levels, and are only briefly activated during specific physiological processes, such as tissue damage repair and embryonic morphogenesis. But cancer cells, through gene mutation, epigenetic reprogramming, and the formation of fusion genes, reactivate and hijack TIM members."

"Different tumor types tend to hijack different members of the TIM superfamily or modify the same member in different ways, which gives them specific identity tags. The functions of this tag include at least: first, maintaining adhesion and communication between tumor cells to form a functional community; second, communicating with specific stromal cells and immune cells in the tumor microenvironment to shape an environment conducive to survival; and third, possibly participating in metabolic reprogramming and the selective formation of metastatic nests."

Song Ziming took a deep breath. The professor was moving too fast. The experiment had only just begun, and he had already theoretically pointed out the precise direction.

"So, our previous research on factor K may actually have only been partially correct. Factor K binding to TIM may also interfere with this identity communication that cancer cells depend on?"

“Correct.” Yang Ping nodded. “That’s why factor K can inhibit tumor growth even without obvious immune cell infiltration. It may directly interfere with signaling.”

Lu Xiaolu then asked, "What about fusion proteins like PAC-FUS1?"

“That’s a more radical form of hijacking.” Yang Ping pointed to a branch on the whiteboard. “Cancer cells not only activate TIM members, but also, through gene fusion, directly and physically connect the TIM core with potent oncogenic functional domains, such as kinases and epigenetic modifying enzymes. This is equivalent to welding the identity lock and the energy switch together, forming a self-sufficient and uncontrolled vicious cycle. This explains why this type of tumor is particularly aggressive and resistant to traditional treatments.”

He turned to face everyone, his gaze piercing: "And the most important conclusion is that since TIM is a superfamily with a common structural origin and functional logic, the design principles for them should also be universal. We don't need to design entirely new K-factors from scratch for every newly discovered TIM variant. We can build a key design rule library."

"Based on the conservative nature of the TIM core structure, we can design a basic key skeleton capable of identifying this conservative region. Then, through a programmable, modular adapter, we can specifically match the variable regions on the surface of different TIM variants. It's like..."

“Like smartphones and different apps!” Griffin blurted out, then covered his mouth in embarrassment.

Yang Ping laughed: "A very apt analogy. The basic hardware (key frame) is universal, but by installing different software (adapters), different locks can be opened. We can even design 'combination keys' or 'master keys' to interfere with multiple related TIM members at the same time, or attack the more vulnerable 'structural joints' that are common to the TIM family."

The lab was buzzing with excitement.

This is not only a theoretical breakthrough, but also an innovation of a completely new theoretical system.

"Professor, should this discovery be published immediately? It would be explosive!" Lu Xiaolu asked excitedly.

Yang Ping nodded, turning his gaze back to the whiteboard.

“I will soon compile this into a paper and publish it in our medical journal. This is just the beginning, a signpost. We have seen the family tree of the ‘locks’ and speculated on the family tree of the ‘keys’. But the real key to unlocking the mystery of cancer treatment…” He paused, then said, word by word, “lies in finding the ‘original blueprint’ that originally designed this ‘lock’, in understanding why life retains such a seemingly dangerous yet universally chosen identification system in cancerous transformation.”

"That may be related to the most fundamental coding of life, to the determination of cell fate, and the construction and reconstruction of organizational order. Cancer may not just be a genetic disease, but also a disease of 'identity' and 'order'."

“And we,” Yang Ping’s voice was soft but clear, “have just touched the knocker of the first door in this maze.”

(End of this chapter)