godfather of surgery

Chapter 1300 Joint Plan
Six o'clock in the morning, in the corridor outside the ICU of Sanbo Research Institute.

Zhou Min curled up in the chair, covered with a thin blanket given to her by Dr. Li Chao from Shanghai. Seven days had felt like seven treads on the edge of a cliff. Her husband, Shen Guohua, was seeing his jaundice subside, regaining consciousness, and his CA19-9 levels were decreasing—a glimmer of hope, but one that was still faint and could be extinguished by the next gust of wind.

Inside the ward, Shen Guohua leaned back, connected to seven or eight tubes. The blood vessels of the artificial liver made a low, rumbling sound as dark red blood flowed from one side, through a cold membrane, and back from the other. His cheeks were sunken, and his eye sockets were deep-set, but a glimmer of light shone in his eyes—a faint ember of life rekindled after the pain had subsided.

"It feels like... the stone in my stomach... has loosened a bit." His voice was hoarse, and he had to catch his breath after every few words.

Xu Zhiliang carefully examined the tension in his abdomen. Indeed, the previously hard left upper abdomen felt softer to the touch. "The tumor may be shrinking, reducing the pressure on the surrounding tissues," he said cautiously, without mentioning the word "effective." In cancer treatment, temporary relief and long-term effectiveness are two different things.

Yang Ping stood in front of the screen, looking at the analysis graph of single-cell sequencing. On the screen, the red dots representing tumor cells were changing: some red dots dimmed, while others changed color, turning a strange purplish-blue, and the combination pattern of surface markers shifted.

“Look here,” Yang Ping pointed to the cluster of purple-blue cells. “These cells downregulate receptor A, which we are targeting, while upregulating receptor B and the immunosuppressive molecule PD-L1. They are learning to evade and trying to silence the immune system.”

“Adaptive resistance.” Song Ziming gasped. “It’s coming faster than we expected, and the mechanism is more complex.”

“If only we had a dual-target vector right now,” Tang Shun sighed. “If we could target both A and B at the same time, they wouldn’t be able to escape so easily.”

"The dual-target prototype in the lab has just completed safety verification in animal experiments, but the efficacy data is not yet available," Xu Zhiliang said, flipping through the report. "Moreover... the entire production process... needs to be rebuilt."

Yang Ping stared silently at the screen, his mind racing with calculations. Shen Guohua's body couldn't withstand a second, intense immune attack, but if the pressure wasn't continued, these tumor cells, which had learned to resist, would proliferate rapidly and make a comeback.

The current approach is actually a transitional one. K therapy for other tumors should have a stable target that is specifically matched with the K factor, just like osteosarcoma.

“Adjust the support plan,” Yang Ping finally said. “Gradually reduce artificial liver support so that his liver can begin to take on metabolic functions. At the same time, prepare small doses of immunomodulators—not an attack, but a gentle nudge. We need to tell those tumor cells: the immune system is still watching, don’t be too arrogant. Give the preparation of the dual-target vector the highest priority; we need to race against time.”

"It's like walking on a tightrope and then adding a balance beam," Song Ziming said.

“So we have to be more careful.” Yang Ping turned to Dr. Li and said, “From today onwards, every vital sign of Mr. Shen, every milliliter of blood biochemistry, and even every emotional fluctuation must be recorded and synchronized to the analysis platform in real time. His body is now the main battlefield for our learning race against the tumor.”

On the same day, at 10:00 AM, at a large conference center in Beijing.

The launch event for Wu Changde's "Open Oncology Targeted Therapy Platform" far exceeded expectations. The hall, which can accommodate 500 people, was packed to capacity, with people standing in the corridors and back rows. In addition to researchers and pharmaceutical company representatives, there were also many investment institutions and media representatives.

On the stage, a huge screen behind Wu Changde displayed the platform's logo: a DNA double helix made up of countless colorful modules, with the words "Openness, Collaboration, Evolution" written below.

"...We believe that the future of cancer treatment does not belong to any single company or laboratory, but to the shared knowledge ecosystem of all humankind." Wu Changde's voice, steady and powerful, resonated throughout the venue through the high-quality sound system. "Therefore, today we are officially opening the Cornerstone 1.0 module library to research institutions worldwide free of charge. It contains twelve validated viral vector backbones, nine types of pro-apoptotic/immune activation gene elements, and a database of identification modules covering 320 common tumor markers."

Applause erupted from the audience, interspersed with hushed murmurs. Making core tools freely available is extremely rare in the domestic and even global biomedical industry.

“Of course, openness does not mean disorder.” Wu Changde changed the subject. “All research using the Cornerstone Module must have its preclinical data returned to the platform’s knowledge base as required. After review by an independent committee, it will serve as the basis for optimizing the next generation of modules. As for the final therapies developed based on the platform, their intellectual property rights belong to the developers and they can be commercialized. We, the platform operators, only charge a symbolic annual maintenance fee.”

A well-known financial journalist raised his hand and asked, "Professor Wu, are your platform and Ruixing Company's K-therapy in competition? What is your view on their technological approaches?"

The question was pointed, and the entire room fell silent.

Wu Changde smiled and said frankly, "First of all, we sincerely admire the pioneering work of Professor Yang Ping's team and Ruixing Company. Like courageous pioneers, they cleaved the first path in the darkness and proved the feasibility of this technological path. Without their success, we would not be standing here today discussing platforms and ecosystems."

He paused, his tone becoming earnest: "But the path pioneers have traversed is often rugged and arduous, and costly. Our goal is to widen, solidify, and illuminate this path, allowing more researchers and pharmaceutical companies to safely and efficiently explore more branches of research and treat more diseases. Therefore, we are not competitors, but road builders and ecosystem builders. In fact, all the cornerstone modules of our platform strictly avoid the core sequences for which Ruixing has applied for patents, and have made fundamental differentiations in design logic. What we hope for is a flourishing of diverse approaches, not a single standout."

The answer was watertight, expressing respect, setting clear boundaries, and painting an enticing picture.

At a small signing ceremony following the press conference, three leading domestic pharmaceutical companies signed strategic cooperation agreements with the platform, and many small and medium-sized enterprises also joined in, as they could obtain substantial funding and technical assistance from the program.

As Wu Changde responded to the congratulations from all sides, his gaze kept glancing at his phone. A short message appeared on the screen from an overseas number: "A beautiful first step. We can begin making contact with the European side."

He turned off the screen, his smile unchanged.

……

That same afternoon, in Geneva, Switzerland, at a café near the World Health Organization (WHO) building.

Lillian Windsor sat by the window, opposite Karl Schmidt, a representative of the German drug regulatory agency, with almost untouched coffee in front of them.

“The interim guidelines have been issued, but the real test has just begun.” Karl stirred his coffee. “We’ve done a preliminary review of the technical proposal for the Frankfurt mirror center. The security level is sufficient, but the definition of data classification and access permissions is very vague. What does ‘minimum scope necessary for clinical decision-making’ mean? Who will make that judgment? In the joint oversight committee, can the Chinese personnel have access to the complete genomic data of European patients? These are all powder kegs.”

“So we need detailed rules, but even more so, we need trust,” Lillian said. “Carl, you’ve been reviewing drugs for twenty years, have you ever seen a global multicenter clinical trial where the data doesn’t leave the country at all?”

"No, but in the past, the data flowed to the United States or Switzerland, within the framework."

“You mean, the flow to China is outside the framework?” Lillian looked him straight in the eye. “Or are we still not ready, deep down, to accept a non-Western technology leader?”

Carl didn't answer, and looked out the window.

“I received an analysis report.” Lillian took a tablet out of her bag and pushed it over.
“If the full approval of K therapy in Europe is delayed by six months due to data issues, according to model projections, at least eight hundred to one thousand eligible late-stage patients will lose their chance for treatment, of whom about one-third could have achieved long-term survival. These are not just numbers, Carl, but eight hundred to one thousand families.”

Carl stared at the simple bar charts and case simulations on the screen, his fingers tightening.

“I’m not trying to emotionally blackmail you,” Lillian said, softening her tone. “I’m stating a harsh arithmetic that regulators often have to face: absolute safety is the ideal, but before that ideal is achieved, lives are being lost. We need to find the best possible balance between the ideal and reality.”

How do you suggest a balance?

“We will accelerate the development of detailed rules, but simultaneously launch an expanded ‘compassionate use’ program.” Lillian was well-prepared. “Before final approval for unrestricted clinical trials and subsequent market launch, we will allow rigorously screened, terminally ill patients with no other options to use K therapy, with full informed consent and close monitoring. The data will also be included in the regulatory framework, thus collecting real-world data from the European population while saving lives. The risks are manageable, and it is ethically sound.”

Carl pondered for a long time: "This requires a high degree of coordination between the EMA and national health departments, as well as a serious commitment from the treatment provider, Ruixing, to bear all additional monitoring costs."

“Mr. Huang Jiacai made a verbal promise to me yesterday that he was willing to take on the responsibility,” Lillian said. “They even proposed that they fund a medical team to cooperate with top European hospitals to establish a dedicated team for compassionate use case monitoring and emergency response. They have already made a good gesture.”

Carl finally picked up his coffee and took a sip; it was already cold. "Lillian, sometimes I feel that you're more like a politician than we are."

“I’m just a woman who doesn’t want to see those looks in the hospital ward anymore.” Lillian looked at the flags fluttering on the WHO building in the distance. “Health is a basic human right. When technology is readily available, any barriers that prevent it from reaching those who need it, whether legal, economic or ideological, are worth our utmost efforts to loosen.”

“Sometimes I feel more and more about our hypocrisy, and more and more about the sincerity of the Easterners. Karl, forgive my bluntness, but if K therapy were American technology, I'm afraid you wouldn't be so cautious. You would definitely give it the green light. So the real obstacle is not safety. Safety is just a hypocritical excuse. The obstacle is prejudice! Is that right?”

Lillian gave a cold laugh.

Carl's face flushed instantly; he had to admit that Lillian was right.

“That’s not how it is…Ms. Windsor!” Carl, of course, wouldn’t admit it. Lillian sneered again: “Your lying has become a habit, your double standards have become a habit, just like energy conservation and emission reduction. Your so-called environmental protection is just a tool to suppress others, while the Chinese are really doing it. Sometimes I hate ourselves. When did we become like this, needing to rely on lies, prejudice and isolation to maintain our so-called thresholds.”

“Oh, Ms. Windsor…”

"No need to say anything more, this is just a private conversation between us. You know I'm telling the truth, but can't you admit it? Are we really already stumbling along?"

……

At night, the Nandu Sanbo Research Institute is brightly lit.

Yang Ping did not participate in any discussions about Wu Changde's press conference; he didn't even have time to watch the news. He and Academician Chen Yongnian's team were engaged in a collaborative research effort spanning time and space.

The video conferencing system connected Southern Metropolis Daily and Beijing. On Academician Chen's side, seven or eight screens in the lab displayed gene maps and affinity simulation data for different serotypes of adenovirus vectors. On Yang Ping's side, the large screen showed Shen Guohua's real-time updates of tumor single-cell sequencing results and immune status analysis.

Yang Ping was well aware that even if this exploration was a stopgap measure, his intuition told him that he could find a stable target for pancreatic cancer that was compatible with factor K in the Explorer, and it was even possible to find another factor K.

“The purple-blue cell population shows a very consistent upregulation of receptor B, which can serve as a second target.” Academician Chen pointed to the data. “Our stock of type 35 vectors has a natural fibrin with moderate affinity for the B receptor. This affinity can be increased by more than fifty times through genetic modification, while maintaining the basic recognition ability of the A receptor.”

“But the logic circuit of the dual-target verification lock must be foolproof.” Yang Ping stared at the gene circuit design diagram. “The AND gate design must be precise. Only when A and B are both highly expressed will the K factor be activated. High expression of either one alone, especially only high expression of B, may accidentally damage normal tissues.”

“We designed a three-level verification process,” Academician Chen explained, “The first level is vector binding; the second level is the recognition of internal environmental signals after endocytosis; and the third level is the final vote of the micro-gene circuit in the cell nucleus. Only when all three levels pass will the K factor be expressed. Theoretically, the probability of false positives can be reduced to less than one in ten million.”

“Theoretically!” Yang Ping repeated these three words, “Shen Guohua’s health cannot afford theoretical errors. We need rapid verification through animal experiments, but time…”

“Use a humanized mouse model,” Lu Xiaolu’s voice broke in. He had just finished another analysis. “We will transplant the frozen tumor cell samples collected from Mr. Shen before his treatment into immunodeficient mice to construct a personalized mouse model. At the same time, we will humanize the liver of the mice to simulate his liver function. Although this new vector cannot completely replace the human body, it can predict safety and efficacy to the greatest extent possible.”

"What is the model development cycle?"

“The fastest is 72 hours,” Lu Xiaolu said. “Our lab has mature processes that allow for parallel operations.”

Yang Ping looked at Academician Chen, who nodded: "We will expedite the preparation and purification of the dual-target vector. We can complete the laboratory-grade product within sixty hours, enough for animal experiments and one human treatment."

“Then let’s get started.” Yang Ping made the decision. “Professor Lu will be in charge of the animal model, Academician Chen will be in charge of the vector, and we will be responsible for all testing coordination and contingency plan preparation. Seventy-two hours later, based on the results of the animal experiments, we will decide whether and when to conduct a second treatment on Mr. Shen.”

The task was broken down, and the laboratory once again entered high-speed operation. Everyone understood that this was not just about saving Shen Guohua alone, but also about validating a completely new technological approach to combat tumor adaptive resistance, the significance of which might be even more profound than K therapy itself.

Song Ziming walked to Yang Ping's side and whispered, "Wu Changde's press conference today was quite grand. The combination of open source, ecosystem, and massive fund support is very attractive."

Yang Ping's gaze remained fixed on the genetic map on the screen: "Don't let public opinion distract you. Our only enemy is the disease; everything else is insignificant."

“I’m worried…” Song Ziming wanted to remind Yang Ping.

Yang Ping withdrew his gaze: "Vector virus, K factor, target—combining these three seems simple, but actually making it is not as easy as they imagine. If they could make it, they would have done it already, without waiting to join our inclusive plan. Vector virus is easy to obtain, K factor is currently unique, and their so-called target is not actually a target in our concept at all. They only have the vector and a useless target, lacking the most important K factor. They think we..."

They assumed that because we produced this data in a year, they could do the same. But they don't realize that obtaining this data would take a normal ten years.

Of course, Yang Ping didn't say these words aloud, which is why Song Ziming was so worried.

……

Forty-eight hours later.

Inside the experimental chamber of Shen Guohua's personalized humanized mouse model.

Twenty mice were divided into four groups: control group, single-target A vector group, single-target B vector group, and dual-target A/B vector group. Twenty-four hours after vector injection...

Single-target A group: tumor growth inhibition rate of 35%, but some mice showed mild elevation of liver enzymes because normal liver cells with low expression of A receptor were attacked.

Single-target B group: tumor growth inhibition rate was only 15%, with no obvious toxicity, because the expression of B receptor on tumors is not yet sufficient.

Dual-target group A/B: Tumor growth inhibition rate of 68%! And no obvious signs of liver or kidney toxicity! Pathological sections showed that a large number of tumor cells underwent apoptosis, while the purple-blue adaptive resistance cells were largely eliminated.

"We succeeded!" a young researcher in Lu Xiaolu's lab couldn't help but exclaim.

But Yang Ping, Lu Xiaolu, and Academician Chen, who were connected via video, did not smile.

"The inhibition rate is 68%, which is good, but 32% of the tumor cells are still surviving." Yang Ping stared at the data. "Let's analyze the characteristics of the surviving cells."

Further analysis quickly emerged: the surviving tumor cells exhibited a third evolutionary path—they simultaneously downregulated receptors A and B, instead highly expressed a very rare receptor C, and entered a state of metabolic dormancy, becoming insensitive to the current immune attack.

"They escaped again." Song Ziming felt a chill. "It's like playing whack-a-mole. You knock one down, and it pops out of another hole. And this time it's even more cunning; it's hiding."

“This is what a tumor is.” Yang Ping’s tone calmed down. “If it were so easy to completely eliminate, it wouldn’t be a medical challenge. Our dual-target attack this time destroyed its main force and the first mutation force, but its staff, the tumor stem cells or highly heterogeneous cells, have already planned a second retreat and dormancy plan. Tumor cells have their own survival methods.”

"Then what do we do? Design a three-target vector targeting the C receptor?" Tang Shun asked.

“It’s too late, and we might get caught in an endless chase.” Yang Ping shook his head. “We need to change our approach. We can’t just rely on externally introduced specific killers. We must activate and arm the patient’s own immune system to the maximum extent so that it can continuously monitor and identify the ever-mutating tumor cells. This is the immune awakening and strengthening program we have been preparing.”

He pulled out a pre-prepared plan: "While using dual-target vector therapy, we will combine it with a combination of low-dose, time-sequential immunomodulators. The goal is not to directly kill the tumor, but rather to: relieve the immunosuppression of the tumor microenvironment and break down defenses such as PD-L1; train immune cells such as T cells in the body to improve their ability to recognize new proteins generated by neoantigen tumor mutations; and change the local metabolic environment on which the tumor depends for survival, making it difficult for those dormant cells."

“It’s like…fighting a joint campaign,” Xu Zhiliang said. “The dual-target carrier is like…precision air strikes to eliminate known main forces; immune regulation is like…ground troops clearing out and occupying territory to establish long-term defenses against stragglers and newly emerging enemies.”

“That’s a good analogy,” Yang Ping nodded. “Mr. Shen’s body is now the entire battlefield. Our previous treatments were like air raids. Now, we need to send ground troops in. The risk is that immune regulation may trigger an autoimmune response or excessive inflammation, so we must precisely control the dosage and timing.”

He looked at Dr. Li Chao and said, "Given Mr. Shen's current liver function and overall condition, assess the risk level of this combined treatment plan."

Dr. Li Chao has been studying the plan for a long time: "The risk is high, but controllable, provided that our monitoring is real-time and accurate."

"What are the wishes of the patient and their family?"

Ms. Zhou said that when her husband was lucid, he repeatedly said: Keep walking forward and don't look back.

Yang Ping closed his eyes, opened them two seconds later, and said with a firm gaze: "Initiate the combined treatment plan."