godfather of surgery

Chapter 1315 Precise Adjustment
Unlike other patients who stayed in hospital rooms, Elena stayed at the Sanbo Hotel.

Every morning at 7:30, she would appear at the research institute building on time, first to have her blood drawn, then to the radiology department for the day's planned examinations. In the afternoon, she would move between different platforms, collecting single-cell sequencing samples, performing metabolomics analysis, and even participating in several functional magnetic resonance imaging (fMRI) scans of the brain to assess the impact of modulatory therapy on the stress response of the central nervous system.

Before the second infusion, the results of the colonoscopy came back.

"Thirty-seven adenomas, the number hasn't decreased, but the shape has changed." Director Xiao of the Endoscopy Center at Sanbo Hospital personally reported to Yang Ping.

The screen displays images of the adenomas before and after treatment side by side. "Before treatment, these adenomas had disordered vascular patterns and unclear boundaries, exhibiting a typical serrated appearance. Now, the vascular patterns of twenty-three of the adenomas have become regular, with clear boundaries, more closely resembling the characteristics of benign tubular adenomas. Pathological biopsy also confirms this: reduced cellular atypia and fewer mitotic figures."

"Regression from high-grade intraepithelial neoplasia to low-grade lesion?"

“That’s one way to put it.” Director Xiao’s tone was incredulous. “Just one low-dose K therapy session showed a trend of pathological reversal. Although the adenomas are still there, they seem to be reversing towards healthy cells.”

More crucial data came from single-cell sequencing. Tang Shun's team analyzed eight thousand cells from the colonic mucosa before and after treatment and discovered a subtle but consistent pattern of change:

Before treatment, the cell population was scattered in the "identity state space" and the TIM expression profile showed high entropy, like a noisy meeting room where everyone was talking loudly but the content was incomprehensible.

After treatment, the cell population showed a "clustering" trend, and the entropy value of the TIM expression profile decreased by 15%. More importantly, the expression levels of the previously disordered "apoptotic component" genes showed a weak negative correlation with the TIM expression level. This is exactly the logical relationship that exists in normal tissues: cells with stable identities do not need to be ready to self-eliminate at any time.

“The system is re-establishing order.” Tang Shun showed a heat map at the discussion meeting. “Although it is still in its early stages, the direction is clear.”

Yang Ping stared at the gradually changing color blocks, his mind drifting back to Elena's analogy of "tuning." A mistuned instrument vibrates with chaotic frequencies, producing harsh noise; only after tuning, when harmonious relationships are established between the frequencies, can the instrument produce a pleasant sound. Now, Elena's colonic mucosal cells seemed to be moving from noise to harmony.

But before the second betting session was about to begin, Elena had an unexpected reaction.

Diarrhea, five to six times a day, watery stools, but no abdominal pain or fever; slight instability in the strength control of the right little finger.

The tests showed that her serum potassium level was at the lower limit of normal, her intestinal inflammation markers were slightly elevated, but her infection markers were negative.

"Is this a treatment-related reaction?" Song Ziming asked worriedly.

After reviewing all the data and comparing them repeatedly, Yang Ping offered his own assessment: "It's not a side effect, but rather part of the regulatory process."

He instructed his team to focus their analysis on single-cell data from Elena's colon biopsy during the diarrhea episode. The results revealed a dramatic shift: just 48 hours before the onset of symptoms, a specific subset of cells in the colonic epithelium, representing approximately 3% of the total, suddenly overexpressed multiple ion channel proteins and water transporters, accompanied by a transient downregulation of tight junction proteins.

"These cells...are actively increasing...intestinal secretions and decreasing...barrier function?" Xu Zhiliang asked, puzzled. "Why...?"

“Emptying!” Yang Ping pointed to another discovery. “In this group of cells, the expression level of TIM dropped sharply, while autophagy-related genes were significantly upregulated. Look here, LC3 fluorescent labeling shows that large-scale autophagy is taking place inside these cells.”

He pieced together all the clues and sketched a possible scenario: Unlike the treatment of late-stage tumors, after the body system regains its ability to recognize these cells, it discovers that some cells have only undergone minor mutations, and the system initiates some kind of reversal regulation, causing these cells to revert to healthy cells; while other cells may have already crossed the reversal threshold, thus initiating a "clearance" process. The clearing method involves altering its own function to promote the expulsion of intestinal contents, thereby flushing itself out.

The human body is truly amazing; its methods are far more sophisticated than existing medical approaches. In the future, medicine should make good use of the body's self-correcting abilities.

To verify this hypothesis, the team designed an experiment: in organoid models, colon organoids from Elena were treated with different doses of the modulator. At low doses, the overall structure of the organoids was more regular and the expression of cell identity genes was more consistent; however, when the dose was increased to a certain threshold, it did induce similar functional changes and autophagy in some cells.

“There is a critical line,” Tang Shun summarized. “If it exceeds the critical line, it cannot be reversed and can only be cleared. If it is still within the critical line, we try to reverse it as much as possible. At the same time, for this kind of precancerous lesion, if the dose is too large, the systemic clearance bias may be greater, while the bias to try to reverse it may be reduced.”

Based on this, Yang Ping's team reduced Elena's second infusion dose by 20%.

After adjustments, the diarrhea symptoms disappeared within two days, and subsequent colonoscopy showed that the adenoma had further "benignized." More importantly, the entropy value of the TIM expression profile decreased by another 10%, and the indicators of system stability continued to improve.

“Once again, factor K is not killing diseased cells,” Yang Ping explained to everyone. “It simply allows the system to re-identify the abnormality of these cells and then self-regulate. Some cells are regulated into normal cells, while others are eliminated by the system because the process is irreversible. The way K therapy treats precancerous lesions is essentially the same as the way it treats cancer—it’s about regulation. The role of factor K is to help the system regain its ability to recognize these cells. Once it can recognize the true identity of these cells, it has the ability to reverse or eliminate them to restore the body to normal.”

In a WeChat group, Mannstein said, "A team from the US NIH contacted me. They are also researching early intervention for Lynch syndrome, but their approach is completely different—they are designing gene-editing tools to try to repair the MSH2 mutation in somatic cells. What do you think?"

Yang Ping pondered for a moment: "Gene editing directly modifies the source code, aiming to solve the problem at its root, which is ideal. However, it is technically difficult, has a high risk of off-target effects, and for adult patients who have accumulated a large number of mutations and epigenetic changes, even if germline mutations are repaired, those acquired disorders may still exist."

He continued, "Our method does not modify genes, but rather utilizes the body's own regulatory system to solve the problem, restore cells to their normal state, and break their disguise. The body's own regulatory ability far surpasses any existing advanced medical technology. Just think how complex and wonderful the natural process from fertilized egg to fetus is; no existing medical technology can replicate this complex process."

However, Einstein's words also inspired Yang Ping. He said, "Most chronic and complex diseases involve more than one layer of problems. This is especially true of cancer: the hardware layer has gene mutations, the software layer has abnormal signaling pathways, and the operating system layer has disordered identity logic. Starting from any local area will only lead to exhaustion. To truly solve the problem, we must make full use of the body's own hidden capabilities."

“Traditional therapies only intervene locally at three levels, attempting to use certain medical techniques to achieve localized intervention. Our approach is different; we start with the entire system, regardless of the level at which the problem occurs. My intervention goal is not to change the localized issue, but to enable the system to recognize the true error, and then let the system handle the rest.” “It’s like discovering a criminal. Traditional therapies try every possible method to apprehend or kill the criminal, considering numerous approaches. Our approach, however, immediately informs the police that the person is a criminal, helping the police identify the criminal, and then leaves the rest to the police.”

Song Ziming continued, "The greatest value of K therapy lies in its full utilization of the body's own regulatory capabilities?"

"Correct!"

Through Elena's case, Yang Ping is now convinced of the correctness of his hypothesis.

Elena made a request, “Can I watch the TIM protein structure resolution process? I want to see what they look like.” Her artistic side was probably starting to stir.

Lu Xiaolu took her to the cryo-electron microscopy center. Behind the safety glass, a huge white machine stood quietly, with an internal temperature as low as -180 degrees Celsius, capturing the ever-changing state of the molecular world.

The screen displays the newly resolved structure of the TIM-F variant from Elena's colon adenoma cells. It is a complex composed of three subunits, resembling a twisted flower with a surface covered with grooves, protrusions, and flexible ring regions.

“The binding site of factor K is here,” Lu Xiaolu pointed to one of the grooves with a laser pointer. “After it binds, it induces the entire structure to rotate about 15 degrees. This rotation is transmitted into the cell through the transmembrane region, just like turning on a switch.”

Elena stared at the slowly rotating molecular model on the screen, remaining silent for a long time.

"What's wrong?" Lu Xiaolu asked.

“It’s beautiful!” Elena whispered. “So complex, so exquisite. A tiny rotation can change the fate of a cell. And I have countless such molecules in my body. Life is truly amazing.”

She turned to Lu Xiaolu: “Your work is like translating the language of life. These structures are letters, and the signaling pathways are grammar.”

People with artistic talent are different; they can express anything intuitively.

A follow-up colonoscopy yielded a decisive result.

"Number of adenomas: reduced by three." Director Xiao of the Endoscopy Center said excitedly, "Only thirty-four remain. All thirty-four have shrunk compared to before. Among them are three flat polyps smaller than 3 millimeters, and the pathology report shows low-grade tubular adenomas. In the area of ​​atrophic gastritis, the endoscopy showed that the mucosa had returned to normal texture, and no intestinal metaplasia was found in the biopsy."

Yang Ping didn't seem very excited: "We need to confirm whether this decline will last or rebound."

Biopsy samples were collected from the regressing adenoma tissues before treatment. The team retrospectively analyzed the single-cell data of these samples and found that those adenomas that eventually regressed shared a common characteristic: their cells exhibited higher "identity state plasticity" before treatment—greater fluctuations in TIM expression profiles and more "open" epigenetic modifications of cell fate-related genes.

“Like a group of confused people, they are more likely to accept new guidance,” Tang Shun analyzed. “And those adenomas that have not regressed have a more ‘rigid’ cellular identity state, which may have formed a stable abnormal homeostasis, requiring stronger regulatory signals or a longer period of time.”

"Therefore, there is a window of opportunity for intervention therapy," Song Ziming summarized. "Intervention when the system is not yet completely solidified in the wrong state is most effective. The earlier the intervention, the less effort is required and the higher the success rate."

Elena's case interim report was published in *Medicine*. Within 24 hours, it was downloaded over 50,000 times, causing a global medical upheaval.

The editor-in-chief of the New England Journal of Medicine personally called Yang Ping, wanting to publish an editorial on Yang's paper. The editorial was titled: "A Shift in the Medical Model: From Confrontation to Regulation."

The article states: "Irena Volkova's case may mark a fundamental shift in how we treat people at high risk for hereditary cancers. In the past, we could only offer monitoring and preventative surgical removal—a fear-based, destructive strategy. Now, we see another possibility: restoring the body's own ability to maintain order through sophisticated systemic regulation, which can not only treat disease but also prevent it. This is not just technological progress, but also a advancement in the medical paradigm."

But then came the criticism, the most pointed coming from a renowned statistical epidemiologist: "A single case report, no matter how brilliant, proves nothing. It could be natural regression, or it could be a placebo effect. We need randomized controlled trials, at least one hundred patients, and five years of follow-up before we can draw conclusions."

Faced with doubts, Yang Ping remained unmoved and proceeded methodically according to his plan.

"Initiate a multicenter clinical trial to recruit more Lynch syndrome carriers, randomly assign them to different groups, and compare the preventive effects of modulated intervention versus standard monitoring."

"Using Elena's time series multi-omics data, we will construct a quantitative predictive model 'from regulatory signal input to disease prevention output.' This model should be able to answer: Given a patient's initial systemic state, what intensity of regulatory signal is needed, and for how long, to stabilize them in a healthy state? Which biomarkers can predict the earliest success or failure of intervention?"

"If we can do this, then in the future when we face high-risk patients, we can first conduct in-depth systemic diagnosis, and then, like prescribing medicine, prescribe a personalized 'adjustment prescription': what molecules, how much dosage, what frequency, to achieve precise adjustment."

Tang Shun, Lu Xiaolu, Song Ziming, and Xu Zhiliang—this team combining basic and clinical medicine is now incredibly enthusiastic because all research indicates that Professor Yang's hypothesis is correct, and its value goes far beyond treating a few cancer patients; it will usher in a new medical paradigm.

This medical model activates or restores the body's self-regulating abilities and enables the body to make precise adjustments.

(End of this chapter)