Introduction

• Cancer is often viewed as a single-cell problem of uncontrolled proliferation, but Levin argues it’s a problem of disrupted *large-scale* coordination.
• Engineered constructs (robots) have a simple top-down architecture and so, cancer is not a problem; in contrast, biological systems consist of multi-scaled architecture in the biological domain where lower organizational levels can and will rebel.
• Cells communicate electrically, forming networks (not just neurons) that process information about anatomical goals. Cancer can be detected, induced, *and normalized* by manipulating these bioelectrical signals.
• Tissues make decisions electrically, and this can be targeted to alter cell behavior, with implications for many areas of medicine.
• High regenerative capacity in animals is correlated with *low* cancer incidence, contrary to some predictions, as the regeneration mechanisms keep cancerous growth suppressed.
• Planarian flatworms exemplify this: they’re immortal, highly regenerative, and cancer-resistant, even with chaotic genomes.

Multicellularity vs. Cancer

• The key question isn’t “why cancer?”, but “why anything *but* cancer?”, given that we’re made of individually competent cells.
• Single-celled organisms have their own agendas; multicellularity requires cooperation toward a larger anatomical “plan”. The human anatomy.
• The genome specifies protein hardware, *not* the overall body plan. The overall body structure, arrangement, type.
• Understanding how cells make collective large-scale decisions is key, not just molecular components, is very limited, as the body plan or the planarian is inherited somatically (with high mutations) and regenerates well with the anatomical bioelectric software playing a cruicial role in addition to the hardware genetics, and that biology, in general is far from fully knowing its large-scale-pattern-making algorthmic mechanisms.
• Homeostasis: the error between normal pattern to errorred is corrected not just in small things such as blood sugar levels, but can and does control big and important, more structural changes in tissues such as limb and face growth in regenerative animals (axolotl limbs and eyes, and frog’s face’s error minimizing rearrangements).
• Homeostatsis works as long as a higher-organizational blueprint exists that dictates the anatomical shape. If this pattern can be manipulated (such as setting thermostat in a house to make a different room-temperature-level), this provides much less difficulty than solving all the underlying molecular problems and errors.

Bioelectricity’s Role

• Scaling competence: evolution upscales the tiny-level agendas to now work, under bioelectric control, together. Cancer is seen as an error of these goals’ breakdown.
• Multicellular goals: Bioelectric signals do not imply and not is cancer a single-cell event: a breakdown in these goals leads to reversion to single-celled, more independent behavior as in Glioblastoma cells.
• All cells have ion channels and voltage gradients across their membranes.
• Different cell types have characteristic voltage ranges. Quiescent cells are polarized; proliferative/cancer cells are often depolarized. However this voltage different alone should not lead to an assumption of it being merely a single-cell-level phenomenon as they work with their other nearby cells, so it is far more complex.
• Like brains, other tissues use bioelectric networks for information processing, acting like a type of anatomical blueprint.
• “Neural decoding” (understanding thoughts from brain activity) can be extended *beyond* the nervous system. Reading and *understanding* electrical signals of tissues.
• An “electric face” pre-pattern in frog embryos prefigures the future anatomy *before* gene expression, suggesting bioelectric instructions exist.
• The pattern can change by using a “voltage-sensitive dye”. Tumors can be detected early as areas of bioelectric disruption (cells decoupling from the network) before full anatomical changes manifest.

Manipulating Bioelectricity

• Tools have been developed to track, model, and, critically, *rewrite* bioelectrical patterns.
• Rewriting: Unlike typical methods involving modifying at a genetic-hardware level, bioelectrical changes is like modifying thermostat setpoints instead of hardware rewiring; it’s a simpler way for “complex” problems.
• This isn’t done with external fields; it uses the cells’ *native* communication mechanisms (ion channels, gap junctions). This can be via drugs, genes, or light to control gap junction and ionic flow.
• The idea that they can guide other processes can be demonstrasted by how ectopic, extra, eyes, or organs, etc, can form anywhere on a frog (they make extra and different types and combinations) using controlled and targetted injections. This is very precise, as cells call neighboring cells into helping, similar to other types of intelligent organisms, such as ants.
• Rewriting these patterns *instructs* cells: Ectopic eyes, limbs, etc., can be induced by recreating specific voltage patterns without genetic changes.
• Cells do not follow hardwire rules; they correct in novel manners until goal is met.
• Even brains with major mutations, and thus defective gene-hardware (example with ‘notch’ mutation, making very structurally poor brains), it can be changed using “bioelectrical-software-override” changes.
• Damaged organs, e.g., those in cases of brain defects, can also be be “repaired”. Even IQ. By overriding gene problems with “bioelectircal set points” using anti-eplieptics.
• Frogs, non-regenerative, induced to re-grow by inducing “pro-regenerative” blastemas, implying, with very brief (1day) exposure to cocktail and without touching it after, a leg would grow out from previously non-leg tissue to near completeion.

Bioelectricity and Cancer Treatment

• This view makes four testable predictions, all supported by evidence:
• 1. Ion channel/pump genes are implicated in cancer molecular data (there should be some gene changes related to channel and protein, confirmed.)
• 2. Bioelectric signatures can be used for early cancer diagnosis (they can and it works).
• 3. Disrupting voltage gradients can *induce* cancer-like behavior (they do; experiment, by disrupting some melanocytes’ voltage communications, it is changed.)
• 4. Modulating voltage gradients can *suppress* cancer. Specifically via electroceutical drugs targetting ionic flows.
• “Augmented-Reality Device” (prototype and potential): helps surgeons via overlays to visually confirm “areas of malignancy and risk”.
• Oncogenes can cause cell disconnection, causing them to pursue selfish behaviors in which their ‘Self’ boundaries become downscaled from its wider self.
• Experiment where, via injecting specific oncogenes, oncogene expression should occur in frogs, however co-injecting ionic channels in some frogs prevent it. They prevent oncogenic changes by correcting the electrical pattern and thus, it could be the physiology and not purely genetics.

Electroceuticals and Future Directions

• “Electroceuticals”: Existing ion channel drugs, guided by computational models, can reprogram cell behavior.
• Focus: Bioelectrical-changes are the software, the instruction layers; thus, its fixes, controls, or overides don’t need to alter hardware genome: it alters only on software-setpoint levels, not in hardware such as Crisper etc.
• Using data from current knowledge of drugs (“drug bank”) + cells with ion channels (“physiomics”), it could target, control and suppress specific growths and patterns.
• This is moving beyond theoretical and early stages. In vitro results with human glioblastoma show promise.
• “Electroceutical Platforms” (Begining stages): drugs may, using a prediction algorithm, get prescribed via predicting what channel types and cells need for correcting cancer.
• Future work involves improving: diagnostics to get early pre-cancer changes. Normalizing cancerous tumors back into normal tissues, and refining controls over mammalian-cell bioelectricity.

引言

• 癌症通常被认为是细胞失控增殖的单细胞问题，但莱文认为这是大规模协调被破坏的问题。
• 工程结构（机器人）具有简单的自上而下的架构，因此，癌症不是问题；相反，生物系统由生物领域中的多尺度架构组成，其中较低的组织层次可以并且将会反抗。
• 细胞通过电进行通信，形成处理解剖目标信息的网络（不仅仅是神经元）。癌症可以通过操纵这些生物电信号来检测、诱导和正常化。
• 组织通过电做出决策，这可以被用来改变细胞行为，对医学的许多领域都有影响。
• 动物的高再生能力与低癌症发病率相关，这与某些预测相反，因为再生机制抑制了癌细胞的生长。
• 涡虫扁虫就是一个例子：它们是不朽的、高度再生的、抗癌的，即使基因组混乱。

多细胞性与癌症

• 关键问题不是“为什么会得癌症？”，而是“为什么不是癌症？”，因为我们是由具有个体能力的细胞组成的。
• 单细胞生物有自己的议程；多细胞性需要向更大的解剖“计划”（人体解剖结构）合作。
• 基因组指定蛋白质硬件，而不是整体的身体计划。 整体的身体结构、排列、类型。
• 理解细胞如何做出集体的大规模决策是关键，而不仅仅是分子组成部分。对这方面的理解非常有限。 身体蓝图或涡虫的蓝图是通过体细胞遗传的（具有高突变），并且通过解剖生物电软件（除了硬件遗传学之外）发挥关键作用而很好地再生，并且总的来说，生物学远未完全了解其大规模模式形成的算法机制。
• 稳态：正常模式到错误的误差不仅在血糖水平等小事上得到纠正，而且可以并且确实控制再生动物（蝾螈四肢和眼睛，以及青蛙面部的误差最小化重新排列）的组织中更大和更重要的结构变化。
• 只要存在指示解剖形状的更高层次的蓝图，稳态就可以发挥作用。 如果可以操纵此模式（例如在房屋中设置恒温器以产生不同的室温水平），与解决所有潜在的分子问题和错误相比，这提供了更少的困难。

生物电的作用

• 扩大能力范围：进化将微观层面的议程升级到现在可以在生物电控制下协同工作。癌症被认为是这些目标崩溃的一个错误。
• 多细胞目标:生物电信号不代表、癌症也不是单细胞事件：这些目标的崩溃导致退回到单细胞、更独立的行为，就像在胶质母细胞瘤细胞中一样.
• 所有细胞都有离子通道和跨膜电压梯度。
• 不同的细胞类型具有特征性的电压范围。静止细胞是极化的；增殖/癌细胞通常是去极化的。然而，仅凭这种电压差异不应导致人们认为这仅仅是单细胞水平的现象，因为它们与其他附近的细胞一起工作，所以它要复杂得多。
• 像大脑一样，其他组织使用生物电网络进行信息处理，就像一种解剖蓝图。
• “神经解码”（从大脑活动中理解思想）可以扩展到神经系统之外。读取和理解组织的电信号。
• 青蛙胚胎中的“电面”预模式在基因表达之前预示了未来的解剖结构，表明存在生物电指令。
• 该模式可以通过使用“电压敏感染料”来改变。肿瘤可以在完全的解剖变化显现之前，作为生物电中断区域（细胞与网络脱钩）被及早检测到。

操纵生物电

• 已经开发出工具来跟踪、建模，以及关键的，重写生物电模式。
• 重写：与涉及在基因硬件层面进行修改的典型方法不同，生物电变化就像修改恒温器设定点而不是硬件重新布线；这是解决“复杂”问题的一种更简单的方法。
• 这不是通过外部场完成的；它使用细胞的天然通信机制（离子通道、间隙连接）。这可以通过药物、基因或光来控制间隙连接和离子流。
• 可以通过青蛙身上任何地方形成异位、额外的眼睛或器官等来证明它们可以指导其他过程的想法（它们制造额外和不同类型和组合），使用受控和有针对性的注射。这是非常精确的，因为细胞会召集附近的细胞来帮忙，类似于其他类型的智能生物，如蚂蚁。
• 重写这些模式可以指导细胞：异位眼睛、四肢等可以通过在没有基因变化的情况下重现特定的电压模式来诱导。
• 细胞不遵循硬连线规则；它们以新颖的方式进行纠正，直到目标实现。
• 即使是具有主要突变、因而有缺陷的基因硬件的大脑（例如具有“notch”突变的例子，导致非常差的结构大脑），也可以使用“生物电软件覆盖”更改来更改。
• 受损器官，例如那些脑缺陷病例中的器官，也可以被“修复”。甚至是智商。 通过使用抗癫痫药物的“生物电设定点”覆盖基因问题。
• 对非再生型青蛙，通过诱导 “促再生”胚基 来促进其生长，这意味着在非常短的时间（1 天）暴露于混合物中并且之后不接触它的情况下，腿会从以前的非腿组织长出来到接近完成.

生物电与癌症治疗

• 这种观点做出了四个可检验的预测，所有这些都得到了证据的支持：
• 1. 离子通道/泵基因与癌症分子数据有关（应该有一些与通道和蛋白质相关的基因变化，已确认）。
• 2. 生物电特征可用于癌症的早期诊断（它们可以而且有效）。
• 3. 破坏电压梯度可以诱发类似癌症的行为（它们确实可以；实验表明，通过破坏某些黑色素细胞的电压通讯，它会被改变）。
• 4. 调节电压梯度可以抑制癌症。具体来说，通过靶向离子流的电药物。
• “增强现实设备”（原型和潜力）：通过覆盖层帮助外科医生，以视觉确认“恶性和风险区域”。
• 致癌基因会导致细胞断开连接，导致它们追求自私的行为，在这种行为中，它们的“自我”边界会从更广泛的自我中缩小。
• 通过注射特定致癌基因进行的实验表明，致癌基因表达应该在青蛙中发生，然而，在一些青蛙中共注射离子通道可以阻止它。它们通过纠正电模式来防止致癌变化，因此，可能是生理学，而不是纯粹的遗传学。

电药物和未来方向

• “电药物”：在计算模型的指导下，现有的离子通道药物可以重新编程细胞行为。
• 重点：生物电变化是软件，即指令层；因此，它的修复、控制或覆盖不需要改变硬件基因组：它仅改变软件设定点水平，而不是像Crisper等硬件中。
• 利用当前药物知识库（“药物库”）+ 具有离子通道的细胞（“生理组学”）的数据，它可以靶向、控制和抑制特定的生长和模式。
• 这正在超越理论和早期阶段。人体胶质母细胞瘤的体外结果显示出前景。
• “电药物平台”（开始阶段）：通过预测纠正癌症所需的通道类型和细胞，可以通过预测算法开出药物处方。
• 未来的工作涉及改进：诊断以获得早期癌前变化。将癌性肿瘤恢复正常组织，并完善对哺乳动物细胞生物电的控制。