避免、治疗与治愈癌症 | Dr. Alex Marson

摘要

Dr. Alex Marson 是加州大学旧金山分校（UCSF）及 Gladstone Institutes 的医师科学家，他与 Andrew Huberman 共同探讨了免疫系统的生物学机制、癌症发生的底层原理，以及正在改变肿瘤学领域的新兴疗法。对话涵盖了可增加或降低癌症风险的实用生活方式因素，以及包括 CAR-T cell therapy 和 CRISPR gene editing 在内的前沿技术——这些技术正从科幻走向临床现实。

核心要点

癌症从根本上是一种遗传疾病 —— 细胞内的基因突变随时间不断积累，导致细胞失去正常调控，开始无序分裂。
最有循证依据的癌症风险因素是吸烟、过度紫外线暴露以及接触农药/化学致突变物；食用色素和烤焦肉类的风险则不那么确定。
有癌症家族史的人都应考虑检测 BRCA 基因突变——尽管它仅占所有癌症的少数，但会大幅提升个人患癌风险。
免疫检查点抑制剂（如 PD-1、CTLA-4 阻断剂）已带来变革性突破，尤其在黑色素瘤治疗方面——包括广为人知的 Jimmy Carter 脑转移病例。
CAR-T 细胞疗法 —— 对患者自身的 T 细胞进行基因改造以靶向癌症 —— 已在儿童及成人白血病/淋巴瘤患者中实现了显著治愈效果。
CRISPR-Cas9 现已能够对 T 细胞进行精准、可编程的基因编辑，开启了工程化免疫疗法的新纪元，相关临床试验正在进行中。
肥胖和高脂饮食似乎从质上改变了免疫应答，而不仅仅是降低免疫数量——并可能导致免疫疗法药物的效果发生变化或降低。
癌症风险随年龄增长而增加，主要是因为在漫长的细胞分裂过程中，突变不断积累，使细胞恶变的概率增大。
即使做到一切正确，仍有可能患癌——它是一种概率性疾病，个体的患病结果绝不应归咎于个人的失败。

详细笔记

免疫系统：核心架构

先天免疫系统

第一道警报系统，由 dendritic cells（树突状细胞）和 macrophages（巨噬细胞）等细胞组成
识别外来或受损物质的通用模式
触发信号分子（cytokines，细胞因子）的释放，招募适应性免疫细胞

适应性免疫系统

主要参与者：T 细胞和 B 细胞（淋巴细胞的类型）
每个 T 细胞表面携带独特的、随机生成的 T 细胞受体（TCR）
TCR 多样性具有概率性——意味着机体携带的 T 细胞甚至能够识别尚不存在的病原体
B 细胞通过类似的随机重组过程产生抗体

胸腺与 T 细胞的”教育”

Thymus（胸腺）是 T 细胞经历筛选的器官
阳性选择：T 细胞必须具备有功能的受体才能存活
阴性选择：意外识别自身组织的 T 细胞会被清除
胸腺随年龄增长而萎缩；对 T 细胞的”教育”在童年时期最为活跃

自身免疫

当正常的检查机制失效，T 细胞或抗体攻击自身组织时发生
示例：
- 关节 → rheumatoid arthritis（类风湿关节炎）
- 产胰岛素的胰腺细胞 → type 1 diabetes（1 型糖尿病）
- 大脑中的髓鞘 → multiple sclerosis（多发性硬化症）
治疗目标：靶向抑制错误定向的免疫应答，而非全面 immunosuppression（免疫抑制）

癌症生物学

什么是癌症

一种遗传疾病，细胞 DNA 中的突变导致其失去正常的生长调控
细胞开始无序分裂，并随时间获得更多突变
转移发生在癌细胞从原发部位扩散到远处器官时——由肿瘤中进一步的进化性遗传改变驱动

突变如何积累

每次细胞分裂都涉及 DNA 复制，而复制并非完美
大多数突变对细胞有害，并触发 programmed cell death (apoptosis)（程序性细胞死亡/凋亡）
偶尔，某个突变赋予细胞生长优势——携带该突变的子代细胞便会繁殖扩增
第二或第三次”打击”可能将轻度异常的细胞转变为真正的癌症

癌症风险随年龄增长

大多数癌症是老年疾病，因为突变积累是一个时间依赖的过程
某些癌症（如特定类型的 childhood leukemia，儿童白血病）在发育阶段早期达到高峰

癌症风险因素

已充分确认的致突变物/致癌物

吸烟 —— 最大的可预防原因；烟草中的化学物质直接损伤肺细胞 DNA
紫外线辐射 —— melanoma（黑色素瘤）和皮肤癌的主要风险因素；晒伤危害尤为严重
农药 —— 农业地区癌症发病率的显著上升提示存在重大风险；该领域研究尚不充分
工作场所/实验室化学品暴露 —— 油漆、稀释剂、溶剂和放射性标记物是真实存在的致突变物
X 射线和电离辐射 —— 在临床背景下是必要的，但低剂量重复暴露（如频繁飞行）可能带来累积风险

遗传易感性

BRCA mutation（BRCA1/BRCA2）大幅提升乳腺癌、卵巢癌及其他癌症的终生风险
部分原因是通过观察到男性乳腺癌患者中携带比例异常高而被发现
检测手段广泛可及，推荐有癌症家族史者进行检测

存在不确定性的领域

烤焦/加工肉类：与 colorectal cancer（结直肠癌）风险相关，但营养学研究方法常受混杂因素干扰
食用色素：动物实验数据存在，但通常是在极高剂量下；在典型膳食暴露量下对人类的相关性尚不明确
超加工食品：总体上可能有害，但针对癌症的机制性数据尚不完整
Dr. Marson 的观点：我们在对环境和膳食致癌物开展严格的人体相关研究方面投入不足

癌症免疫疗法

免疫检查点抑制剂

癌细胞可通过激活 T 细胞上的天然”刹车”（通过 PD-1、CTLA-4 通路）来”伪装”自己
阻断这些刹车的药物（检查点抑制剂）能够释放已有的 T 细胞，使其攻击肿瘤
最具代表性的成功案例：melanoma（黑色素瘤）—— Jimmy Carter 的脑转移经检查点抑制剂治疗后消退
目前已在多种癌症类型中获批并应用

CAR-T Cell Therapy

从患者体内提取 T 细胞，通过基因改造使其表达嵌合抗原受体（CAR）——一种在实验室中人工设计的受体
CAR 被设计用于靶向癌细胞上的特定蛋白质
改造后的 T 细胞像输血一样重新回输体内，“编程”后追杀癌细胞
靶点示例：CD19，一种存在于 B 细胞白血病和淋巴瘤上的蛋白质
首位儿童患者：Emily Whitehead，2012 年 8 岁时在宾夕法尼亚大学接受治疗，彼时白血病已用尽所有治疗方案，接受 CAR-T 细胞治疗后进入缓解——目前正在 UPenn 读医学预科
最初的递送方式使用慢病毒载体（改造后的 HIV 病毒）将 CAR 基因插入细胞

早期 CAR-T 的局限性

慢病毒插入不精确——DNA 随机整合
对血液系统肿瘤（白血病、淋巴瘤）效果良好，但对实体瘤（如胰腺癌、脑癌）效果欠佳
实体瘤微环境具有免疫抑制性，能抵抗 T 细胞的活性

CRISPR 基因编辑

起源

发现于细菌对抗噬菌体病毒的免疫防御系统
细菌利用 CRISPR 扫描 DNA，识别病毒序列并将其切断
Jennifer Doudna 和 Emmanuelle Charpentier 认识到这一系统可被重新编程为通用基因编辑工具——因此荣获诺贝尔奖

CRISPR-Cas9 的工作原理

Cas9：一种充当分子剪刀的蛋白质，用于切割 DNA
向导 RNA：一种可编程的 RNA 分子，引导 Cas9 到达特定的 DNA 序列
向导 RNA 可被设计为匹配任何基因组靶点，可在线订购，并在数天内递送至细胞
切割完成后：可以删除基因、dis

English Original 英文原文

Avoiding, Treating & Curing Cancer | Dr. Alex Marson

Summary

Dr. Alex Marson, a physician-scientist at UCSF and the Gladstone Institutes, joins Andrew Huberman to discuss the biology of the immune system, the mechanisms underlying cancer development, and emerging therapies that are transforming oncology. The conversation spans practical lifestyle factors that increase or decrease cancer risk, and cutting-edge technologies including CAR-T cell therapy and CRISPR gene editing that are moving from science fiction to clinical reality.

Key Takeaways

Cancer is fundamentally a genetic disease — mutations accumulate in cells over time, causing them to lose normal regulation and divide uncontrollably.
The biggest evidence-based cancer risk factors are smoking, excessive UV exposure, and pesticide/chemical mutagen exposure; food dyes and charred meat carry far less certain risk.
Everyone with a family history of cancer should consider testing for BRCA mutations, which dramatically elevate individual cancer risk even though they represent a minority of all cancers.
Checkpoint inhibitor immunotherapy (e.g., PD-1, CTLA-4 blockers) has been transformative, particularly for melanoma — including the well-publicized case of Jimmy Carter’s brain metastases.
CAR-T cell therapy — genetically engineering a patient’s own T-cells to target cancer — has produced remarkable cures in pediatric and adult leukemia/lymphoma patients.
CRISPR-Cas9 now enables precise, programmable gene editing of T-cells, opening a new era of engineered immunotherapies currently in clinical trials.
Obesity and high-fat diets appear to qualitatively alter immune responses, not just reduce immune quantity — and may cause immunotherapy drugs to work differently or less effectively.
Cancer risk increases with age primarily because mutations accumulate over time across many cell divisions, making transformation more probable.
You can do everything right and still develop cancer — it is a probabilistic disease, and individual outcomes should never be attributed to personal failure.

Detailed Notes

The Immune System: Core Architecture

Innate Immune System

The first-alarm system, consisting of cells like dendritic cells and macrophages
Recognizes generic patterns of foreign or damaged material
Triggers release of signaling molecules (cytokines) that recruit adaptive immune cells

Adaptive Immune System

Major players: T-cells and B-cells (types of lymphocytes)
Each T-cell carries a unique, randomly generated T-cell receptor (TCR) on its surface
TCR diversity is probabilistic — meaning the body carries T-cells capable of recognizing pathogens that don’t even exist yet
B-cells produce antibodies through a similar random recombination process

The Thymus and T-Cell Education

Thymus is the organ where T-cells undergo selection
Positive selection: T-cells must have a functional receptor to survive
Negative selection: T-cells that accidentally recognize the body’s own tissues are eliminated
The thymus shrinks with age; its education of T-cells is most active in childhood

Autoimmunity

Occurs when normal checks fail and T-cells or antibodies attack the body’s own tissues
Examples:
- Joints → rheumatoid arthritis
- Insulin-producing pancreatic cells → type 1 diabetes
- Myelin in the brain → multiple sclerosis
Therapeutic goal: targeted suppression of only the misdirected immune response, not blanket immunosuppression

Cancer Biology

What Cancer Is

A genetic disease where mutations in a cell’s DNA cause it to lose normal growth regulation
Cells begin dividing uncontrollably, acquiring further mutations over time
Metastasis occurs when cancer cells spread from the original site to distant organs — driven by further evolutionary genetic changes in the tumor

How Mutations Accumulate

Every cell division involves DNA replication, which is imperfect
Most mutations are harmful to the cell and trigger programmed cell death (apoptosis)
Occasionally a mutation confers a growth advantage — those daughter cells propagate the mutation
A second or third “hit” may convert mildly abnormal cells into full-blown cancer

Cancer Risk Increases With Age

Most cancers are diseases of later life because mutation accumulation is a time-dependent process
Some cancers (e.g., certain childhood leukemias) peak early during developmental periods

Cancer Risk Factors

Well-Established Mutagens/Carcinogens

Smoking — the largest preventable cause; chemicals in smoke directly damage lung cell DNA
UV radiation — major risk factor for melanoma and skin cancers; sunburn is particularly damaging
Pesticides — cancer rate spikes seen in agricultural regions suggest significant risk; understudied
Workplace/lab chemical exposures — paints, thinners, solvents, and radioactive labels are real mutagens
X-rays and ionizing radiation — necessary in clinical contexts, but low-dose repeated exposures (e.g., frequent flying) may confer cumulative risk

Genetic Predisposition

BRCA mutation (BRCA1/BRCA2) dramatically elevates lifetime risk of breast, ovarian, and other cancers
Identified partly because men who developed breast cancer disproportionately carried it
Testing is widely available and recommended for those with a family history of cancer

Areas of Uncertainty

Charred/processed meats: Implicated in colorectal cancer risk, but nutritional study methodology is often confounded
Food dyes: Animal data exist at very high doses; human relevance at typical dietary exposure is unclear
Ultraprocessed foods: Likely harmful broadly, though mechanistic cancer data are incomplete
Dr. Marson’s view: We are under-investing in rigorous human-relevant studies of environmental and dietary carcinogens

Cancer Immunotherapy

Checkpoint Inhibitors

Cancer cells can “cloak” themselves by activating natural brakes on T-cells (via PD-1, CTLA-4 pathways)
Drugs that block these brakes (checkpoint inhibitors) unleash existing T-cells against tumors
Most celebrated success: melanoma — Jimmy Carter’s brain metastases resolved with checkpoint inhibitor treatment
Now approved and used across multiple cancer types