godfather of surgery

Chapter 1318 You Need to Top Up

To further verify the hypothesis, Yang Ping's expanded "new plan" was launched with the ethical approval of many countries. As the number of volunteers increased, the first adverse reaction was reported.

The patient, a 42-year-old Swedish man and Lynch syndrome carrier, case number P-009, developed high fever, a generalized rash, and a sharp increase in liver function markers 72 hours after receiving his first personalized infusion of Elena at only one-fifth of the initial dose. Emergency hospitalization was initiated, and infection and other drug-related factors were ruled out, pointing to a serious immune-related adverse reaction.

“Catching is an early sign of a cytokine storm,” the lead researcher in charge of the center reported in an emergency video conference, his tone somber. “Although it was controlled with hormones and biologics and was not life-threatening, we had to remove him from the study. Biopsy showed that his gut TIM expression pattern was unusual, with a large number of unconsidered splicing variants.”

Silence fell over the meeting room. This was an inevitable hurdle in large-scale clinical trials, but when it actually happened, especially when "systemic regulation" was highly anticipated and considered a milder and safer approach, the impact of the first serious adverse reaction was particularly strong.

“Our modulator is essentially a foreign protein, and one that has been artificially modified. Any artificially manufactured drug or protein factor is bound to have defects, especially the first-generation factor K used for Lynch syndrome.” Yang Ping broke the silence, his voice calm. “It binds to TIM and changes its conformation, which itself may be recognized as a neoantigen by the immune system, especially in cases where certain individuals have specific TIM variants. We considered avoiding known highly immunogenic sequences in our design, but the data base for personalized designs is still too thin to exhaust all variants. Accumulating data is also the goal of our experiments.”

He pulled up all the baseline data for P-009 and compared it side-by-side with Elena's. "Look here, Elena's TIM-F variant is mainly concentrated in the two loop domains of the extracellular region, where our regulator is designed for mild binding. The P-009 variant, on the other hand, has an additional glycosylation site near the transmembrane region, which may affect the overall conformation after regulator binding, exposing a previously hidden immune epitope."

Lu Xiaolu raised a key question: "Is this an isolated case, or does it indicate a blind spot in our personalized design strategy? Do we need to perform a comprehensive immunogenicity prediction for every patient? That would cause the cost and time to increase exponentially."

“Perhaps we need to change our approach,” Tang Shun said slowly, staring at the data. “It’s not about pursuing absolute non-immunogenicity, which is probably unrealistic. Instead, it’s about learning to manage the immune response, just like with immunotherapy. Our modulators triggered an unwarranted strong immune attack, which means the regulatory signals themselves were misunderstood by the immune system. Could we design a buffer or guidance system to deliver the regulatory signals more gently, or simultaneously provide trace amounts of immune regulatory signals to guide the immune system to recognize them as allies rather than enemies? While improving the level of immune management, we can iterate on the relevant K factors, continuously improving them in the process, reducing or even eliminating this adverse immune response.”

After discussions within the team, they began to conceive of a second-generation regulatory strategy: no longer a single "regulator molecule," but a "smart regulatory system," potentially including master regulatory proteins, delivery carriers such as nanoparticles that respond to specific microenvironments, and synergistic immune microenvironment regulatory components. The complexity increases dramatically, but safety may also be significantly improved.

The P-009 incident was swiftly and transparently communicated to all trial centers and regulatory agencies. Surprisingly, very few participants withdrew. Many expressed in their feedback that they understood the risks of cutting-edge research and were willing to contribute data to "safer future therapies."

Another reason is that traditional treatments are simply too poor, and the risks associated with Yang Ping's new therapy are negligible. Even if such risks do occur, the effectiveness and safety of the treatment far surpass those of traditional therapies.

This incident and its handling were reported by the British Medical Journal as a case study of "transparency and trust building in high-risk, cutting-edge clinical trials." Science, in the face of setbacks, has ironically highlighted its rational and responsible nature.

……

The craze for the Yellow Emperor's Inner Classic has not subsided and is showing a trend of intensifying.

A Silicon Valley startup has launched a health monitoring and lifestyle guidance app called "Vital Flow." Its selling point isn't directly referencing the *Huangdi Neijing* (Yellow Emperor's Inner Classic), but rather claiming that its core algorithm is "inspired by the wisdom of traditional Eastern holistic medicine." It combines data from wearable devices bundled with the app, such as heart rate variability, sleep structure, skin conductance, activity levels, and users' daily simple symptom, mood, and dietary logs, using machine learning to generate personalized "system status daily reports" and "fine-tuning suggestions" for users.

The "Daily Report" won't give a diagnosis like "You have high blood pressure," but instead will show suggestions such as "Today your system is in a 'hyper-excited' state, it is recommended to add 30 minutes of gentle walking and reduce spicy food at dinner" and "The 'repair' index has been low over the past week, which may be related to poor sleep continuity, try to start your sleep preparation process 15 minutes earlier."

These suggestions resemble an advanced version of life coaching, but the underlying logic attempts to mimic a simplified "systemic balance" model. The company has hired several scientists with medical backgrounds and an expert with research in Traditional Chinese Medicine as consultants.

This product quickly gained popularity among tech elites and health enthusiasts due to its trendy concept and seamless user experience. The company attracted over $100 million in venture capital.

Song Ziming also bought one to try out. In fact, it was not much different from those health bracelets, except that it had a so-called "adjustment model" added and then commercialized.

“This shows the market’s hunger,” Song Ziming commented after the trial. “People are tired of fragmented health checkup indicators and the paradox of feeling uncomfortable even when everything is normal. They crave a tool that can understand their overall physical condition and provide integrated advice. Our scientific research explores the principles at the top level, while the market is already trying to apply the concept of ambiguity at the bottom level.”

Yang Ping was also powerless to do anything about it: "Innovation by the public can inspire ideas, but it can also bring risks due to a lack of rigor. The key is that we need to use solid research to establish more scientific and verifiable systematic health assessment standards as soon as possible. Those products that are too vague or wrong will naturally be eliminated."

After such products appeared in the United States, a domestic company also launched a similar product. The domestic product is more advanced and more user-friendly than the American product. It can score the user's health balance status every day, and the score can be accurate to two decimal places. This has attracted users like moths to a flame because they firmly believe that such accurate scores must be supported by strong technological capabilities.

Because of the popularity of Yang Ping's theory, doctors and researchers at Sanbo Institute who participated in "systemic regulation" research became the focus of attention for some companies. They tried to offer these researchers large sums of money to endorse their products, even just for a brief appearance or a few words, to prove that their products were true practitioners of regulation theory. However, none of these researchers paid any attention to these invitations; they remained focused on their research.

……

Studies on the T-SEED complex have found that, in cell models derived from APECED patients, artificially enhancing a certain functional conformation can indeed slightly improve its presentation efficiency of limited self-antigens, and a slight increase in the proportion of apoptotic cultured autoreactive T cells was observed. While the effect is far from sufficient to treat the disease, it at least represents a small step towards making the "regulation of the immune tolerance induction process theoretically possible."

However, an unexpected discovery diverted some attention.

In their study of control cells, the team observed positive changes in the functional state of the T-SEED complex when thymic epithelial cells were treated with very low doses of regulators targeting TIM homologous proteins. These changes were accompanied by an increase in the secretion of small immunomodulatory signaling molecules. This suggests a possible unknown coordination and communication between the TIM-related identity maintenance system and the T-SEED-related immune tolerance induction system in healthy systems. Perhaps, at a higher level, maintaining self-identity and recognizing oneself from others share two aspects of the same underlying logic!

This potential cross-system connection led Yang Ping to deeper reflection.

Individual health is a complex network of nested and interconnected layers. The falsification of identity for cancer, the misjudgment of identity for autoimmune diseases, and even the ambiguity of identity for aging may all stem from "signal distortion" or "connection failure" at different nodes and to varying degrees in this deep network.

Organized by Einstein, Yang Ping was invited to participate in a small, high-level online summit called "The Metaparadigm of Medicine: Beyond Reductionism." Attendees included Nobel laureates, leading philosophers, basic medical scientists, and clinical medical scientists, among others.

At the conference, a complex systems expert with a physicist background presented a model based on multi-agent simulation. In the model, tens of thousands of "virtual cells" possess simplified state rules and communication methods. He demonstrated how the system self-organizes from a chaotic state into an ordered structure when a simulated "regulation signal" is introduced, and how this ordered structure resists a certain degree of disturbance.

“Living systems are undoubtedly among the most complex adaptive systems on Earth,” the physicist said. “Traditional medicine attempts to intervene with linear causal pushrod models. But perhaps a more effective approach is to understand its self-organizing rules and then apply tiny guiding fields, like using a magnetic field to guide iron filings to form patterns. In my view, Professor Yang’s team’s regulation theory is precisely trying to define and apply such guiding fields.”

One philosopher of science raised an ethical challenge: "If regulation means engaging in dialogue with the body's systems and guiding their self-repair, then who leads this dialogue? A doctor's authority is based on professional knowledge, but the body's voice—biosignals—needs to be interpreted. In the future, will we see a kind of symbiotic doctor who understands medicine, data science, and patients' life narratives, helping to find the optimal regulatory path between technological possibilities and personal values? What impact will this have on medical education and doctor-patient relationships?"

In response to the question, Yang Ping said, "The future you described is one of the directions we are striving for. Medicine will increasingly become an art that integrates science, technology, and humanities. Doctors may no longer be the sole decision-makers, but rather interpreters, coordinators, and enablers. We need to cultivate a new generation of health practitioners who can understand the complexity of systems, communicate with data, and empathize with patients. This is very difficult, but it may be the next revolution that medicine must face after breaking through technological bottlenecks."

During a break in the meeting, an elderly man with a full head of white hair contacted Yang Ping privately. He was James Fitzgerald, a pioneer who first supported the "biopsychosocial model of medicine" in the 1970s, and is now over eighty years old.

“Young man,” Fitzgerald said excitedly, “I have been following your work for a long time. I am very pleased to see that systems biology and complexity science are finally beginning to have a substantial impact on medical practice. Back then, we proposed to pay attention to psychological and social factors, but we lacked the tools to firmly link them with biological mechanisms. What you are doing now is building that bridge.”

He paused, his voice lowering slightly: "But be careful, every shift in the medical paradigm will encounter enormous resistance from vested interests and ingrained habits of thought. The healthcare industry, the insurance system, medical education, and even public perception are all built on the old 'warfare model.' Your 'dialogue model' is more elegant and may be more effective, but it requires the entire system to change the way it speaks, which is much harder than discovering a new molecule."

Yang Ping nodded solemnly: "I understand, Professor Fitzgerald. So what we are working hard on is not only laboratory discoveries, but also clinical validation, tool development, standard setting, and what you said—changing the way we have a dialogue. This is a multi-dimensional long march."

The old man encouraged Yang Ping: "Keep your courage and keep your patience. Scientific breakthroughs are sometimes like lightning, but social acceptance is often like the tide, with its ebb and flow. But the direction of the tide is ultimately determined by the moon's gravity, which is the truth and better health outcomes. You are becoming a part of that gravity."

After the meeting, Yang Ping once again recalled his research process on system regulation theory.

Initially, he only wanted to solve a specific scientific problem—how the K factor works—which then evolved into a theoretical hypothesis—identity verification and system regulation. Now, this hypothesis is drawing on broader issues about the nature of medicine, the definition of health, technological ethics, and even social systems.

As the research grew increasingly massive, Yang Ping decided he had to scale back. He needed to focus on the theory itself, and let others handle the various derivative studies that arose from it.

The hypothesis itself is a vast topic, and he decided to extend the research beyond the Sanbo Institute. He wanted to bring together all the research institutes and laboratories of the entire Nandu Medical University system to complete this research.

Having sat for too long in the meeting, Yang Ping got up and went for a walk. Some PhD students who were resting in the lab were discussing a domestically produced system adjustment wristband.

"Look, my score today is 90 points, which is higher than 99% of users nationwide. Don't let my weight fool you..."

This guy is over 200 pounds and has high blood pressure, high cholesterol, and high blood sugar, yet he still got such a high score.

"Let me see, how come your health score is higher than mine?"

Another person didn't believe it because they had been an athlete since childhood and still exercise, and were as strong as an ox, yet they only scored in the 60s.

"How come you got such a high score? Mine is so much lower than yours!"

You need to top up your account!

(End of this chapter)