godfather of surgery

Chapter 1308 Can tumors really be conquered?

Sanbo Research Institute Conference Room.

When Yang Ping walked in, everyone noticed the difference. His eyes didn't show the fatigue from staying up all night; instead, they sparkled with excitement.

"Everyone," Yang Ping said, standing directly in front of the main screen without sitting down, "Recently, we have collected more than 5,000 samples, analyzed hundreds of TIM structural variants, and observed dozens of K factor modes of action. We have been asking one question: What exactly is the working principle of K therapy?"

"Everyone must be wondering, didn't we already figure out the principle of K therapy? The combination of K factor and adenovirus infects tumor cells of specific tumors, then invades the cells, and K factor initiates apoptosis of tumor cells."

"Yes, that's right, but that's just the surface phenomenon. My previous research on it was only superficial."

"Let's not forget that our discovery of Factor K was quite accidental, just like the discovery of penicillin. Was penicillin really that simple: a drug that could kill some tumor bacteria? It's not that simple. As research on penicillin deepened, all sorts of antibiotics emerged, and human medicine began to conquer bacterial infections."

"The same applies to Factor K. If we can unlock its true secrets, we might be able to conquer tumors."

Yang Ping pulled up a simple diagram with a "lock and key" model on it.

“Initially, we thought that TIM was the lock and the K factor was the key. Once the lock was opened, the door would open, and the tumor cells would be marked, invaded, and eliminated.” Yang Ping paused for a moment. “But this model cannot explain many phenomena. Why do different tumors require different key variants? What are their underlying rules? We know nothing. Just like why penicillin is effective against some bacteria but not others, we cannot be satisfied with just that penicillin can kill some bacteria.”

Song Ziming frowned in thought, Lu Xiaolu already had a premonition, and Tang Shun quickly took notes.

Yang Ping switched screens, and a brand new diagram appeared: a complex three-tiered system.

“I believe,” Yang Ping’s voice was clear and firm, “that TIM is not a lock, but the user interface of an authentication system. Cancer cells use this interface to continuously send status reports to the internal and external environments, saying ‘I am a normal cell, everything is fine.’”

He pointed to the second layer: "Below this interface is the cell's identity maintenance program, a complex set of algorithms that ensures the cell is in the correct position, performing the correct function, and maintaining the correct metabolic state. This program connects all the cell's core systems: the energy factory mitochondria, the protein workshop endoplasmic reticulum, the genetic information repository nucleus, and the immune recognition module MHC."

“And at the very bottom,” Yang Ping emphasized, “is the order maintenance protocol built into the evolution of all multicellular life. The core idea of ​​this protocol is that any cell that loses its correct identity, cannot perform its correct function, or threatens the overall order must be eliminated. Apoptosis, autophagy, pyroptosis, immune clearance—these are all procedures for executing the protocol. Factor K only initiated one of these procedures, and it was too accidental that we obtained and utilized it.”

The conference room was silent. The last time the professor was this excited was when he proposed the three-dimensional guided gene theory.

“Cancer cells become cancer cells,” Yang Ping continued, “not because they invent something new, but because they hijack the user interface, forge authentication reports, and thus deceive the underlying order maintenance protocol—look, I am a normal cell, don’t eliminate me.”

He pulled up data from three key cases: "And the K factor is a mandatory verification instruction."

"When the K-factor binds to TIM with extremely high affinity, it doesn't simply 'label' it, but instead sends the highest priority alert to the entire system: 'Warning! Authentication error! User interface hijacked! Initiate underlying protocol verification!'"

Song Ziming suddenly looked up: "So... the different effects of different K-factor variants."

“It depends on which specific execution path of the underlying protocol they trigger,” Yang Ping continued. “Some are directly connected to the apoptosis program, like in the case of childhood osteosarcoma, where factor K binds to and pulls the intracellular tail of TIM, physically triggering the apoptosis switch on the mitochondria. Some trigger the immune visibility restoration program; in the case of melanoma, factor K alters the TIM conformation, affecting neighboring MHC molecules. Some trigger the protein quality control program; in the case of pancreatic cancer, factor K exposes abnormal proteins, making them recognized by the autophagy system.”

Lu Xiaolu took a deep breath: "This means that, theoretically, as long as we find the connection points between the TIM structure and the various paths of the underlying protocol, we can design a specific K-factor to precisely select which cleanup path to trigger?"

“Not only that,” Yang Ping’s eyes gleamed even brighter, “but more importantly, if we understand the complete logic of this underlying protocol, we may find a universal way to awaken cancer cells. Instead of designing a special key for each type of tumor, we can learn to use a mother tongue that cancer cells can understand and cannot refute to issue the same ultimate command to all cancer cells: identity forgery, execute elimination.”

"Although it's still a long way off to achieve that, I believe we will be able to do it someday."

The atmosphere in the conference room was instantly ignited.

Tang Shun was the first to react: "Those tumors that have a tendency to regress spontaneously! Their TIM systems are unstable, probably because their user interface hijacking technology is not mature enough, making it easier to trigger alarms on the underlying protocol?"

“Correct.” Yang Ping nodded. “So our next step is not to continue collecting samples in a general way, but to conduct targeted and in-depth investigations.”

He pulled up a new task list and clearly planned the next steps in his research:
"Tang Shun focused on analyzing all spontaneously regressing or well-differentiated tumor samples to find the precise correlation between their TIM expression profiles, conformational dynamics, and cell fate checkpoint gene expression. I need to know under what circumstances the alarm threshold of the underlying protocol is lowest."

"Lu Xiaolu suspended all new structural analyses and concentrated all cryo-electron microscopy and molecular dynamics simulation resources to capture the millisecond-level dynamic trajectory of TIMs in three key cases. We want to see the real process of TIM conformational changes when the K factor binds, especially the torsion of the transmembrane region and the displacement of the intracellular region—that is the mechanical lever for signal transduction."

"Song Ziming coordinated the experimental platform to establish a multi-level verification system. From molecular interactions, cell phenotypes, organoid responses to mouse models, we verified our theory step by step. In particular, we designed experiments to prove that the effect of factor K is indeed achieved by triggering intrinsic programs rather than external killing."

Yang Ping looked at everyone: "If this theory is correct, we will not only find new anti-cancer targets, but we will also discover the deepest vulnerability of cancer cells—they must rely on the hijacking of normal life systems to survive, and this hijacked system itself has backdoors."

"What we need to do is find that back door and then knock on it."

Song Ziming was filled with excitement: "So, we really can conquer tumors?" "Let's give it a try, what if we succeed?" Yang Ping said with a smile.

Tang Shun's eyes were filled with admiration for the professor. No wonder he wasn't afraid of others stealing his technology. It was useless. He had just spent a lot of effort stealing bits and pieces of technical information and hadn't even fully understood it when the theory on this side was completely innovated, and all his investment on that side went down the drain.

Next, everyone settled down and began to readjust the resources of the entire laboratory. Some people continued to study the original topics, while others focused on the research tasks assigned by Professor Yang.

By conducting single-cell multi-omics analysis on 37 neuroblastoma samples with a tendency for spontaneous regression, Tang Shun and his team discovered a surprising pattern: within these tumors, there are two distinctly different cell subpopulations.

Subgroup A highly expresses the classic TIM variant (TIM-L1) and proliferates actively, but it also highly expresses a group of genes called "apoptotic preparatory components." The protein products of these genes are normally in an inhibited state, but once they receive a specific signal, they can rapidly assemble into apoptosis execution machinery.

Subgroup B: TIM expression is low or atypical, cell cycle is arrested, showing differentiation or senescence characteristics, while "prepared apoptosis component" genes are silenced.

"It's like," Tang Shun reported to Yang Ping, his words tumbling out in excitement, "like cancer cells of subgroup A playing with fire. They hijacked the TIM system to maintain their proliferation, but because the hijacking wasn't perfect, they ended up putting themselves on the edge of a volcano. Their survival signal system and their self-destruct mechanism are separated by only a thin barrier!"

Almost simultaneously, Lu Xiaolu brought even more shocking news.

Using the latest ultra-high-speed cryo-electron microscopy technology and artificial intelligence-assisted molecular dynamics simulation, they successfully captured the entire process of K-factor combined with TIM. Although it is not a true real-time video, through millions of instantaneous frozen samples and algorithm reconstruction, they obtained a near-realistic dynamic trajectory.

In the conference room, Lu Xiaolu used 3D holographic projection to demonstrate this miracle.

As can be seen, the K-factor acts like a precisely guided missile, approaching a specific surface groove in the TIM. The bonding is not a static "insertion keyhole," but rather a series of precise conformational inductions:
Several key loop regions of factor K come into contact with the flexible region of TIM; the extracellular domain of TIM undergoes a subtle rotation; this rotation is transmitted into the cell via the α-helix of the transmembrane region; the intracellular short tail (only 15 amino acids) is pulled, twisted, and its angle is changed; this changed short tail forms a stable contact with the activation domain of an apoptosis initiation protein called BAK on the outer mitochondrial membrane.

“Look here,” Lu Xiaolu zoomed in on the key area, “TIM’s intracellular short tail is normally dynamic and disordered. But after the K factor binds, it is ‘straightened’ and fixed into a specific conformation. And this conformation is geometrically complementary to the activation interface of the BAK protein.”

He pulled up the pre-calculated interface analysis: "Electrostatic complementarity 0.85, shape matching degree 0.92. This is not a coincidence, it's almost like it was designed."

“It wasn’t designed,” Yang Ping said softly. “It’s a legacy of evolution. BAK is one of the core executors of apoptosis, and its activation requires release from an inhibited state. I guess that in normal cells, the correct conformation of certain TIM family members may itself be part of the inhibitory signal of BAK, with the cell identity normal and apoptosis prohibited. After cancer cells hijack TIM, they incorrectly maintain this conformation and incorrectly inhibit BAK.”

“And the K factor,” Lu Xiaolu continued, “unexpectedly relieved this erroneous inhibition by forcibly altering the TIM conformation.”

Yang Ping closed his eyes, his mind racing with data.

This isn't a simple trigger, but rather a correction. Cancer cells attempt to survive by exploiting the normal rules of the life system, evading the immune system's surveillance and elimination, but flaws emerge in the process of imitation. K therapy doesn't attack, but rather points out these flaws, allowing the system to repair itself.

“We need to prove the direct causal relationship of this ‘inhibition relief’.” Yang Ping opened his eyes. “The next thing we need to do is: construct an in vitro binding system between the intracellular short tail of TIM and BAK, and measure the change in binding strength before and after K factor treatment. Then we will conduct cell experiments: if we mutate the intracellular tail of TIM so that it cannot be induced by K factor allosteric changes, we will see if K factor can still induce apoptosis.”

“It’s already underway,” Song Ziming said, holding a tablet. “Preliminary in vitro results support your hypothesis. And,” he said with a complicated expression, “Professor, you need to see the latest data from the mouse experiments yourself.”

The group hurriedly arrived at the animal experiment center.

In an SPF-grade animal facility, thirty human tumor xenograft mice were divided into six groups. One group was inoculated with a pediatric osteosarcoma cell line that is highly sensitive to factor K. According to the experimental design, they should show tumor shrinkage after factor K treatment, but not complete regression, since this was only a single-agent treatment.

But the sight before them shocked everyone: the tumors in three of the mice had completely disappeared.

It's not shrinking, it's not scarring, it's complete disappearance, leaving the skin smooth as usual, with only very slight pigmentation under the skin.

“We replicated the pathological sections,” a postdoctoral researcher in charge of the animal experiments said, his voice trembling. “There were no residual tumor cells. What’s even stranger is that the muscle tissue in the area that was originally invaded by the tumor showed signs of regeneration. The newly formed muscle fibers were neatly arranged and had a normal striated structure.”

“That’s impossible,” Lu Xiaolu said subconsciously. “Factor K has no tissue repair function; it can only act on tumor cells.”

Yang Ping pondered for a moment, his gaze deep, "Unless the way the tumor cells are eliminated activates the regeneration process of the surrounding normal tissue."

He quickly retrieved the full monitoring data for this group of mice, and suddenly remembered something: "The tumor inoculation sites in these mice?"

"The hind limbs and thighs are infiltrated with deep muscles."

“We need to compare tumor samples from other groups of mice at the same time point,” Yang Ping said, quickening his pace. “I want to see the immune cell infiltration in the tumor microenvironment, the extracellular matrix remodeling, and especially the activation status of the remaining normal muscle satellite cells.”

(End of this chapter)