godfather of surgery

Chapter 1309 System Error Correction
A few days later, the new experimental results came out.

Completely consistent with theoretical predictions: Extremely unique microenvironmental changes were found in this group of mouse tumor samples that achieved complete remission:

Tumor cell apoptosis occurs through immune-silencing apoptosis, without the release of large amounts of pro-inflammatory factors, but instead releases anti-inflammatory and repair-promoting signals; tumor-associated fibroblasts transform from a pro-cancer phenotype to a regenerative phenotype and begin to secrete healthy extracellular matrix; surviving muscle satellite cells are activated and express myogenic differentiation markers; and even newly formed capillary buds have been observed.

“This is not simply about killing,” Yang Ping said, presenting the data at the discussion. “It is an orderly handover.”

He took a deep breath, trying to describe the discovery in the most accurate terms:

“When factor K triggers the tumor cell identity verification-elimination procedure in a specific way and at a specific time, it does not cause chaotic necrosis and inflammation, but instead initiates a programmed exit mechanism. The dying tumor cells release repair signals, resetting the microenvironment from a state that supports tumor growth to a state that supports tissue regeneration.”

“This means,” he said, looking around the room, “that if we can precisely control the clearance pathway and intensity triggered by factor K, we may achieve not just tumor elimination, but tumor elimination accompanied by tissue repair. This is true cure, not just tumor-free.”

A long silence fell over the room.

This prospect is so shocking that it exceeds everyone's most optimistic imagination. If these words hadn't come from Professor Yang's mouth, no one would have believed it.

“But this is just an isolated case,” Tang Shun cautioned. “Three mice, one type of tumor, and a specific inoculation site.”

“So we need to expand our validation,” Yang Ping nodded, “but first we need to understand the principles behind these individual cases. Why this type of tumor? Why this location? Which specific pathway is triggered by factor K that leads to this orderly withdrawal?”

He assigned a new task: to comprehensively analyze all molecular events in this fully remission mouse model, from the binding of tumor cells to the eventual disappearance of tumor cells, including transcriptomics, proteomics, metabolomics, epigenetics, time-series sampling, and single-cell resolution.

“We need to draw a complete molecular pathway map for this miraculous cure,” Yang Ping said. “If this path exists, we must find it, understand it, and then replicate it; otherwise, we will forever be stuck on the surface.”

The global sample collection has never stopped, but the focus has shifted from breadth to depth. Yang Ping requires that every sample with a special response, whether it is complete remission, rare side effects, or unexpected concomitant effects, undergo the most in-depth multi-omics analysis.

At the same time, theoretical models are also iterating rapidly.

Yang Ping further refined his "three-layer model," proposing a theoretical framework for cellular identity status: each cell exists in a state space defined by three coordinates: identity confirmation is the degree to which the cell expresses the correct identity marker (the function of the TIM system); functional adaptation is the cell's ability to perform its intended function; and order conformity is the degree to which the cell contributes to the overall tissue order. Normal cells exhibit high values ​​in all three dimensions.

Cancer cells attempt to compensate for their poor functional fit and negative order compliance by hijacking the identity verification system and increasing false readings in Dimension 1.

The role of the K factor is to forcibly correct the identity verification readings, revealing the true low values ​​of dimensions 2 and 3, thereby triggering the order maintenance protocol.

Based on this framework, Yang Ping's team began to try to do something unprecedented: to use this hypothesis theory to make some predictions.

Instead of predicting which gene mutation will cause cancer, it predicts which K factor variant will act and in what way for a given TIM variant-expressing tumor, which clearance pathway will be most likely to be triggered, and what kind of subsequent microenvironmental effects will be produced.

This requires integrating all knowledge from structural biology, systems biology, computational biology, and clinical medicine.

For Yang Ping's experiment, the Digital Medicine Laboratory at Nandu Medical University specially built an artificial intelligence-assisted system called "Life Logic Simulator".

The system’s first real-world test was conducted on a special sample sent by Dr. Catherine from MD Anderson Cancer Center: a liver metastasis biopsy specimen from a patient with advanced colon cancer who was resistant to all seven targeted therapies and two immunotherapies and was theoretically incurable.

Within 72 hours of the sample's arrival, Sanbo completed rapid sequencing and structural prediction of TIM, a rare TIM-F subfamily variant with only three similar records in the database.

The model team inputs the data into the "Life Logic Simulator".

The system ran for six hours, integrating 1297 parameters including the tumor's transcriptome characteristics, microenvironment composition, and the patient's systemic immune status, and ultimately output three recommended strategies:

Strategy 1 (42% probability): Design a K factor variant targeting a specific loop region at the C-terminus of this TIM variant to predict potential triggering of endoplasmic reticulum stress-related non-classical apoptosis;

Strategy 2 (probability 31%): Design a bispecific K factor that can bind to both TIM and adjacent PD-L1, predicting that it may simultaneously trigger apoptosis and restore T cell killing.
Strategy 3 (18% probability): Design penetrating K factor to attack the transmembrane region of TIM and predict the possible induction of cell death via the lysosomal pathway.

"Why are the probabilities so low?" Song Ziming asked.

“Because this is a highly drug-resistant, advanced tumor,” Yang Ping explained, “its system has undergone multiple evolutionary selections, hijacking deeper and having more backup pathways. Our model honestly says: there is no strategy that guarantees success.”

Which one should we choose?

Yang Ping stared intently at the detailed molecular mechanism predictions for the three pathways.

Strategy 1 is the most direct, but it may be resisted by the existing stress tolerance mechanisms of tumors; Strategy 2 is the most ingenious, but it is difficult to design and has a long production cycle; Strategy 3 is the most novel, but it may also be toxic to normal cells.

"I'll do all three," Yang Ping decided, "but I'll prioritize the third."

Everyone looked at him.

"Professor, what are your reasons?"

Because everyone feels they can no longer keep up with the professor's pace.

“From an evolutionary perspective,” Yang Ping pulled up the model’s in-depth analysis, “if a tumor has become resistant to so many targeted and immunotherapies, it means it has evolved strong defenses against extracellular attacks. But penetrating the cell membrane and attacking from within is a front it may not be fully prepared for. Moreover, lysosomal cell death typically releases fewer pro-repair signals, making it more suitable for this late-stage, highly malignant condition.” He paused. “More importantly, if we want to verify the universality of the underlying protocol theory, we need to test different types of alarm signals. Transmembrane attack is a form of physical damage, a stronger systemic intrusion alarm than conformational changes. If even this kind of signal can be recognized by the underlying protocol and translated into a clearance command, then the foundation of the theory is even more solid.”

However, designing a penetrating K factor requires overcoming two major challenges: first, enabling large protein molecules to cross the cell membrane, and second, ensuring precise binding to the target after penetration. They drew inspiration from viral membrane-penetrating peptides and antibody penetration techniques to design a pH-sensitive conformational switching K factor: under the acidic conditions of the tumor microenvironment, it exposes both the membrane-penetrating sequence and the target sequence; upon entering the neutral pH environment of the cell, the membrane-penetrating sequence is hidden, while the target sequence is fully exposed.

Without a new theory, designing a K-factor would be unimaginable. The first K-factor was simply a natural occurrence, discovered by chance.

Song Ziming, Tang Shun, and Lu Xiaolu felt that their knowledge was insufficient. They were very confused by what the professor was saying, and could not even understand it at all.

"Professor..." Tang Shun had no choice but to bring it up.

Yang Ping waved his hand: "It's okay if you don't understand for now. Just do as I say. I'm eager to know the conclusion of each time. I'll explain it to you in detail when I have time later."

It took a week from design to the production of the first batch of experimental proteins.

The results of in vitro experiments were encouraging: the half-maximal inhibitory concentration (IC50) of this novel K factor against drug-resistant colon cancer cells was one-fiftieth that of the conventional K factor, and indeed a large number of cells were observed to die via the lysosomal rupture pathway.

But the real test is in animal models.

The mice with human tumor xenografts showed a dramatic response after treatment began: the tumors shrank rapidly by 50% in the first three days, then entered a plateau phase, and began to shrink a second time on the 7th day. By the 14th day, the tumors had completely disappeared in four of the six mice, and the remaining tumors in the other two were less than 10%.

Pathological analysis showed that tumor cells did indeed undergo large-scale lysosomal cell death, but contrary to prediction, the death process was relatively orderly and did not trigger severe local inflammation. The remaining tumor bed showed significant fibrosis and vascular degeneration, but no significant regeneration of normal tissue was observed.

“Partially consistent, partially deviating,” Yang Ping examined the data, “but the key is that it worked. We achieved complete or near-complete remission in a multidrug-resistant terminal disease model, even though it was an animal experiment, and under the most ideal conditions.”

He raised his head, his eyes resolute: "This means that our theoretical framework is predictive. For the first time, we designed an effective treatment strategy not through trial and error, not through luck, but through an understanding of the systemic logic of cancer cells."

The first practical test of the "Life Logic Simulator" didn't yield a perfect score, but it was enough to prove that we're on the right track.

Just as the Sanbo team was immersed in the excitement of the breakthrough, Dr. Catherine remained silent for a full hour after receiving the treatment results report for the drug-resistant colon cancer sample, and then made an overseas call to Yang Ping.

“Professor Yang,” Dr. Catherine lowered her voice, “last week at a small symposium on tumor systems biology in Zurich, two people gave very interesting keynote speeches. One was from the Max Planck Institute in Germany, who cited the cancer cell identity state hypothesis; the other was from MIT, who was developing a quantum computing model for cell fate decision-making. Both speeches cited several papers recently published by your team.”

"In those papers, you proposed a new tumor classification framework that is not based on gene mutations, but on cell state stability and identity signal entropy. Many people didn't notice it at the time, but now these two speakers have."

“I know science is open, but business and politics are not,” Dr. Catherine said bluntly. “Professor Yang, if you are really close to a fundamental discovery that could guide the design of the next generation of therapies, spies from big pharmaceutical companies, spies from competitors, and even national intelligence agents will soon smell it.”

“I have received academic collaboration offers from three top pharmaceutical companies, with suspiciously generous terms. They are all subtly inquiring about Sanbo’s latest developments. I haven’t said anything, but others may not.”

After hanging up the phone, Yang Ping convened a confidential meeting with his core team.

“Dr. Catherine’s reminder is correct,” Yang Ping said. “Once our theoretical framework is fully published, it will change the entire logic of anti-cancer drug development. From finding targets to attack to understanding systemic intervention, this is not just a technological upgrade, it is a revolution. And revolutions always encounter resistance from vested interests. This is not the first or second time we have encountered such a situation.”

"Then what do we do?" Song Ziming asked.

Yang Ping said slowly, "We are accelerating, but strengthening confidentiality in key areas. All raw data will remain on local servers, physically isolated. The core algorithm module of the life logic simulator is encrypted. Only a few of us know the corresponding relationships of the sample codes for key experiments."

He paused for a moment: "But most importantly, we need to complete the decisive verification of the theory as soon as possible."

"What kind of decisive verification?" Lu Xiaolu asked.

Yang Ping pulled out a plan that he had secretly prepared for several weeks.

The title is: "The Ultimate Verification of the 'Identity Authentication' Theory: Its Clinical Application in Human Cancer Patients."

Three to five patients with advanced cancer who have failed conventional treatment and have a life expectancy of less than three months are selected. Based on a detailed analysis of their tumors, a fully personalized K factor variant is designed using a "life logic simulator" for compassionate use therapy.

“This is not a clinical trial,” Yang Ping emphasized. “This is a proof of principle. We want to prove that, based on our theoretical framework, we can accurately predict which intervention strategy is effective for which type of tumor and achieve the theoretically predicted efficacy.”

This is extremely risky. Failure is not just a failure of treatment, but also the falsification of the theory. But success will be a beacon illuminating the entire field.

“The patient screening criteria are extremely strict,” Yang Ping continued. “It must be a genuine failure of last-line treatment, there must be a complete tumor molecular profile, there must be clear TIM expression, and we must be psychologically and ethically prepared for failure.”

“More importantly,” he looked at everyone, “this must be purely scientific research, without any commercial interests involved, and all expenses must be borne by the research institute.”

"If it succeeds," Tang Shun said softly.

“If we succeed,” Yang Ping continued, “we will prove for the first time in history that cancer can be understood as a systemic logical error and can be treated through systemic error correction, which will usher in a completely new era.”

(End of this chapter)