Michael Levin Bioelectricity 101 Crash Course Lesson 9: Planarian Regeneration: The Secrets of the Immortal Worm Summary

• Planarians are flatworms with extraordinary regenerative abilities. They can regrow entire bodies from tiny fragments.
• This regeneration is not just “healing”; it’s the complete rebuilding of missing tissues and organs, perfectly restoring form and function.
• Planarians have a large population of adult stem cells called neoblasts, which are responsible for their regenerative capacity.
• Bioelectricity plays a crucial, instructive role in planarian regeneration, guiding the activity of neoblasts and determining the body plan.
• Voltage gradients act as a “map” or “blueprint” that specifies the location and identity of missing body parts.
• Gap junction communication is essential for coordinating bioelectric signals and cell behavior across the planarian body.
• Manipulating bioelectric signals (e.g., by blocking gap junctions or altering ion channel activity) can dramatically alter regeneration, leading to two-headed worms, worms with no heads, or worms with heads of different species.
• Planarians provide a powerful model system for studying regeneration and understanding how bioelectricity controls large-scale anatomical form.
• Planarian “body-plan” has the attributes of a memory. It can be overriden.

Michael Levin Bioelectricity 101 Crash Course Lesson 9: Planarian Regeneration: The Secrets of the Immortal Worm

Let’s journey into the world of one of the most remarkable creatures on Earth: the planarian flatworm. These seemingly simple animals, often found in freshwater ponds and streams, possess an ability that has captivated scientists for centuries: they can regenerate their entire bodies from even tiny fragments. This isn’t just healing a wound; it’s the complete rebuilding of missing tissues, organs, and even a head, all perfectly restored to their original form and function. They’re effectively “immortal” in the sense that they don’t seem to age and can theoretically live indefinitely through regeneration.

Imagine if you could cut yourself in half and each half would grow into a complete, independent you. That’s essentially what planarians can do. If you cut a planarian crosswise, the head piece will regrow a tail, and the tail piece will regrow a head. You can even cut them into many small pieces, and, under the right conditions, each piece will regenerate into a complete, albeit smaller, planarian. This is regeneration on an almost unbelievable scale.

What makes this possible? Several factors contribute to planarians’ incredible regenerative abilities, but we’ll focus on the key players:

1. Neoblasts: Planarians have a large population of adult stem cells called neoblasts. These are pluripotent cells, meaning they have the potential to differentiate into any cell type in the body. Neoblasts are distributed throughout the planarian body and are constantly dividing, providing a ready supply of cells for both normal tissue turnover and regeneration. Think of them like a built-in repair crew, always on standby.
2. Pre-existing tissues can revert to stem-cells. Besides the stem cells, regular adult cells can revert, that is, to regain some capabilities of a stem cell to take on other tissues roles!
3. Bioelectricity: The subject that all of our course, thus far, have built towards.
4. Absence of Aging. Planaria can be chopped into tiny fragments. Despite going through intense and repeated damage, they keep re-generating their tissue. The mechanisms normally associated with aging seem entirely bypassed by them, a topic also deeply tied into Bioelectricity, and also the collective coordination and communication across cells (like tumors, where damaged cells detach from the whole and form growths), all orchestrated via gap junctions.
5. Fast Speed of Changes.
6. No need of External Growth Cues:. Unlike, say, animal regrowth (limb restoration) seen on some amphibians, the frog’s body will use many outside signals for cues. Planaria has all that information in their body!
7. Ability to “learn”, then regenerate that info even without heads.
8. Their Genetic “blueprint” can be modified and those altered information maintained. Bioelectricy enables manipulation and setting up persistant body instructions

How does regeneration actually work in planarians? Let’s walk through the process, highlighting the crucial role of bioelectricity:

1. Injury: When a planarian is cut, the first thing that happens is wound closure. The tissues at the cut edges contract, minimizing tissue loss and preventing infection.
2. Bioelectric Changes: Immediately after injury, dramatic bioelectric changes occur at the wound site. Ion channels open and close, altering the flow of ions and changing the membrane potential of cells. Gap junctions are modulated, controlling the communication between cells. These changes create a specific bioelectric pattern at the wound. This happens in minutes. This isn’t some byproduct; experiments show that interupting this crucial, rapid shift of electric signals severely disables any organized tissue growth at all!
3. Blastema Formation: A mass of undifferentiated cells, called the blastema, forms at the wound site. The blastema is composed of neoblasts that have migrated to the wound and begun to proliferate.
4. Bioelectric Guidance: The bioelectric pattern at the wound site acts as a “map” or “blueprint” for regeneration. It provides positional information to the neoblasts, telling them:
   • “What’s missing?” (e.g., head, tail, part of the body)
   • “Where am I?” (e.g., anterior, posterior, medial, lateral)
   • “What should I become?” (e.g., head cell, tail cell, muscle cell, etc.)
   • “What size should the tissue become?”
5. Cell Proliferation, Migration, and Differentiation: The neoblasts, guided by the bioelectric pattern, proliferate, migrate to the correct locations, and differentiate into the appropriate cell types to rebuild the missing structures.
6. Pattern Reformation: As the new tissues grow, they re-establish the normal bioelectric pattern of the planarian body. This is a dynamic process; the bioelectric pattern changes over time, reflecting the changing anatomy of the regenerating worm.

The most compelling evidence for the instructive role of bioelectricity in planarian regeneration comes from experiments where researchers manipulate the bioelectric signals:

• Gap Junction Blockage: Michael Levin and his colleagues have shown that by blocking gap junctions (using drugs that prevent connexin proteins from forming channels), they can dramatically alter regeneration. For example, if you cut a planarian in half and block gap junction communication at the wound site of the tail piece, it can regrow a head instead of a tail, creating a two-headed worm. This shows that the bioelectric signals flowing through gap junctions are essential for determining the polarity of the regenerating tissues (which end is head, which end is tail).
• Ion Channel Manipulation: Altering the activity of specific ion channels can also have profound effects. For instance, changing the membrane potential of cells at the wound site can influence the type of structures that regenerate.
• Permanent bioelectric memory: What is especially remarkable about two headed Planarians is this trait is “locked in”. Subsequent cuttings (without use of further drugs, for instance) will regrow two heads again. The body’s ‘plan’ have changed and the circuit is now closed into a self-sustaining pattern.
• Two-headed Planaria showing _other_ Species’ Head shapes: Levin and his lab changed not only how many head grew, but its underlying species’ shape. The underlying “instruction” can thus persist, yet still vary considerably!
• Creating “Headless” Worms: In some cases, blocking gap junctions or altering ion channels can prevent regeneration altogether, or lead to the formation of worms with no head.

These experiments demonstrate that bioelectricity is not just a consequence of regeneration; it’s an active regulator that controls the process. The bioelectric pattern is like a software program that specifies the body plan, and by manipulating this program, researchers can alter the outcome of regeneration.

Planarians are a fantastic model system for studying regeneration for several reasons:

• Their regenerative abilities are exceptional.
• They are relatively simple organisms, making it easier to study the cellular and molecular mechanisms of regeneration.
• They are easy to maintain and manipulate in the lab.
• They have a well-characterized genome.

By studying planarians, we can gain fundamental insights into the process of regeneration, and these insights could have profound implications for human medicine. If we can understand how planarians regrow entire bodies, we might be able to develop therapies to stimulate regeneration in humans, potentially allowing us to regrow lost limbs, repair spinal cord injuries, or regenerate damaged organs.

Michael Levin Bioelectricity 101 Crash Course Lesson 9: Planarian Regeneration: The Secrets of the Immortal Worm Quiz

1. What makes planarians remarkable?

A) They are very large.
B) They can regenerate their entire bodies from small fragments.
C) They can fly.
D) They are brightly colored.

2. What are neoblasts?

A) A type of virus that infects planarians.
B) Adult stem cells that are responsible for planarian regeneration.
C) The structures that form gap junctions.
D) The cells that make up the planarian’s head.

3. What is a key property of planarian neoblasts?

A) They can only become nerve cells.
B) They’re already fully differentiated.
C) They are pluripotent, capable of differentiating into any cell type.
D) They lack ability to respond to bioelectricity.

4. True or False: Planarian regeneration is simply wound healing, not true regeneration.

A) True.
B) False

5. What role does bioelectricity play in planarian regeneration?

A) No role.
B) A passive role, simply reflecting the genetic program.
C) An instructive role, guiding the activity of neoblasts and determining the body plan.
D) An entirely destructive force.

6. What is the blastema?

A) A weapon
B) A tumor that develops.
C) A mass of undifferentiated cells that forms at the wound site.
D) An opening

7. What does the bioelectric “map” at the wound site tell the neoblasts?

A) “What’s missing?” and, where to go.
B) “Where am I?”
C) “What should I become?”
D) All of the above.

8. What happens if you change/influence the bioelectric landscape in regenerating Planaria

A) Nothing happens, their DNA overrides any and all influence.
B) It will not matter since bioelectricity and voltage changes only occur during frog, but not worm development
C) Profoundly altered growth and regeration patterns emerge.
D) Only the neoblast’s location shifts.

9. What happens if you block gap junction communication in a regenerating planarian tail piece?

A) It might regrow a tail, as normal
B) It regrows its gut
C) It can regrow a head instead of a tail, forming a two-headed worm.
D) Nothing

10. True/False Planarian that grow two heads because of blocked Gap Junction, retain a bioelectric ‘memory’, and will always create two-headed offspring from then on, when it reproduces.

A) True.
B) False.

11. How could planarian regeneration research potentially benefit humans?

A) It might lead to therapies to stimulate regeneration in humans.
B) It could help us understand how to prevent aging.
C) It could lead to new treatments for cancer.
D) All of the above.

12. Scientists think regeneration process occur by:

A) Signals to cells on the body blueprint from chemicals
B) Bioelectricity
C) Bioelectric + Chemical messaging
D) Just Stem-cells acting alone.

13. After it’s injured/cut, what immediately occurs for planaria?

A) Chemical pathways begin altering genes.
B) Nothing.
C) Bioelectrical changes (taking only minutes) establishing key new changes to signal correct and approporiate reconstruction to neoblasts.
D) Bioelectric patterns form a few weeks after

14. What occurs after the bioelectric changes that follows cutting the planaria?

A) Neoblasts starts forming an undifferentiated clump of mass.
B) A mass (called “Blastema”) assembles together to help regrowth of missing tissue
C) Both of the Above
D) None of the Above

15. Which parts of the cell coordinate to establish body-plans for regenerating worms?

A) The combined actions between ion channels, ion pumps, and also cell connectivity between gap junctions.
B) Neoblasts.
C) Genetic instructions and Chemical Pathways.
D) Both B and C

16. Which animals can regrow brain tissues?

A) Axolotls (salamanders).
B) Humans
C) Rats.
D) All of the above.

17. Compared to humans, what best captures how well planarians restore their bodies:

A) They regrow like normal “scar tissue”.
B) A blastema does not occur in these situations.
C) It restores lost parts perfectly.
D) It grows 2 or 3 body-segments where only 1 should exist.

18. What are these creatures (and their close “relatives”) being called?

A) Nothing in particular.
B) “Aliens”, with mysterious biologies.
C) Immortals.
D) “Time travellers”

19. A two-headed planaria can do what next?

A) If left to reproduce (fission), two headed planaria can create two-headed lines of organisms that would remain that way despite subsequent interference.
B) If left to itself (without reproduction), it can spontaneously regrow into a normal Planarian.
C) The planaria turns back into its original state and cannot live for more than a week.
D) None of the Above.

20. By blocking only gap-junction communication, with no other alterations, what outcome has occurred before in worms?

A) Regrow of new limb where none should be
B) Altered positioning.
C) Creation of different “head shapes”.
D) None of the above

Michael Levin Bioelectricity 101 Crash Course Lesson 9: Planarian Regeneration: The Secrets of the Immortal Worm Answer Sheet

1. B

2. B

3. C

4. B

5. C

6. C

7. D

8. C

9. C

10. A

11. D

12. C

13. C

14. C

15. A

16. A

17. C

18. C

19. A

20. C

迈克尔·莱文 生物电 101 速成课程 第九课：涡虫再生：不死蠕虫的秘密 摘要

• 涡虫是具有非凡再生能力的扁虫。它们可以从小碎片中再生出整个身体。
• 这种再生不仅仅是“愈合”；它是对缺失组织和器官的完全重建，完美地恢复了形态和功能。
• 涡虫有大量称为新生细胞的成体干细胞，这些细胞负责它们的再生能力。
• 生物电在涡虫再生中起着至关重要的指导作用，指导新生细胞的活动并确定身体形态。
• 电压梯度充当“地图”或“蓝图”，指定缺失身体部位的位置和身份。
• 间隙连接通讯对于协调涡虫体内的生物电信号和细胞行为至关重要。
• 操纵生物电信号（例如，通过阻断间隙连接或改变离子通道活动）可以显着改变再生，导致双头蠕虫、无头蠕虫或具有不同物种头部的蠕虫。
• 涡虫为研究再生和了解生物电如何控制大规模解剖形态提供了一个强大的模型系统。
• 涡虫的“身体形态”具有记忆的属性。 它可以被覆盖。

迈克尔·莱文 生物电 101 速成课程 第九课：涡虫再生：不死蠕虫的秘密

让我们进入地球上最引人注目的生物之一的世界：涡虫。 这些看似简单的动物，通常在淡水池塘和溪流中发现，拥有一种吸引了科学家几个世纪的能力：它们甚至可以从微小的碎片中再生出整个身体。 这不仅仅是伤口愈合； 它是对缺失组织、器官甚至头部的完全重建，所有这些都完美地恢复到其原始形态和功能。 从某种意义上说，它们实际上是“不朽的”，因为它们似乎不会衰老，并且理论上可以通过再生无限期地生存。

想象一下，如果你可以把自己切成两半，每一半都会长成一个完整的、独立的你。 这基本上就是涡虫可以做的事情。 如果你横向切割涡虫，头部会重新长出尾巴，尾部会重新长出头部。 你甚至可以将它们切成许多小块，并且在适当的条件下，每一块都会再生出一个完整的、尽管较小的涡虫。 这是一种几乎令人难以置信的再生规模。

是什么使这成为可能？ 有几个因素促成了涡虫令人难以置信的再生能力，但我们将重点关注关键因素：

1. 新生细胞： 涡虫有大量称为新生细胞的成体干细胞。 这些是多能细胞，这意味着它们有可能分化成体内的任何细胞类型。 新生细胞分布在整个涡虫体内，并且不断分裂，为正常的组织更新和再生提供充足的细胞供应。 可以将它们想象成一个内置的维修团队，随时待命。
2. 现有组织可以恢复为干细胞。 除了干细胞外，常规成体细胞可以恢复，也就是说，重新获得干细胞的某些能力以承担其他组织的角色！
3. 生物电：到目前为止，我们所有课程的主题都是建立在这个基础上的。
4. 不衰老。 涡虫可以被切成微小的碎片。 尽管经历了强烈而反复的损害，它们仍然不断再生它们的组织。 通常与衰老相关的机制似乎完全被它们绕过了，这个话题也与生物电密切相关，还有细胞之间的集体协调和通讯（如肿瘤，受损细胞从整体中脱离并形成生长物），所有这些都是通过间隙连接精心策划的。
5. 变化速度快。
6. 无需外部生长线索：。 与在某些两栖动物身上看到的动物再生（肢体恢复）不同，青蛙的身体会使用许多外部信号作为线索。 涡虫体内有所有这些信息！
7. 能够“学习”，然后在没有头的情况下也能再生这些信息。
8. 它们的遗传“蓝图”可以被修改，并且这些改变的信息可以被保留。 生物电可以操纵和设置持久的身体指令

涡虫的再生实际上是如何工作的？ 让我们逐步了解这个过程，强调生物电的关键作用：

1. 损伤： 当涡虫被切割时，首先发生的是伤口闭合。 切割边缘的组织收缩，最大限度地减少组织损失并防止感染。
2. 生物电变化： 损伤后立即，伤口部位会发生剧烈的生物电变化。 离子通道打开和关闭，改变离子流并改变细胞的膜电位。 间隙连接被调节，控制细胞之间的通讯。 这些变化在伤口处产生特定的生物电模式。 这发生在几分钟内。 这不是什么副产品； 实验表明，中断这种关键的、快速的电信号转变会严重破坏任何有组织的组织生长！
3. 胚基形成： 在伤口部位形成一团未分化的细胞，称为胚基。 胚基由已迁移到伤口并开始增殖的新生细胞组成。
4. 生物电引导： 伤口部位的生物电模式充当再生的“地图”或“蓝图”。 它为新生细胞提供位置信息，告诉它们：
   • “缺少什么？” （例如，头部、尾部、身体的一部分）
   • “我在哪里？” （例如，前、后、内侧、外侧）
   • “我应该变成什么？” （例如，头部细胞、尾部细胞、肌肉细胞等）
   • “组织应该变成什么大小？”
5. 细胞增殖、迁移和分化： 新生细胞在生物电模式的引导下增殖、迁移到正确的位置并分化成适当的细胞类型以重建缺失的结构。
6. 模式重组： 随着新组织的生长，它们会重新建立涡虫身体的正常生物电模式。 这是一个动态过程； 生物电模式会随着时间的推移而变化，反映出再生蠕虫不断变化的解剖结构。

生物电在涡虫再生中起指导作用的最令人信服的证据来自研究人员操纵生物电信号的实验：

• 间隙连接阻断： 迈克尔·莱文和他的同事已经表明，通过阻断间隙连接（使用阻止连接蛋白形成通道的药物），他们可以显着改变再生。 例如，如果你将涡虫切成两半并阻断尾部伤口部位的间隙连接通讯，它会重新长出头部而不是尾巴，从而形成双头蠕虫。 这表明通过间隙连接流动的生物电信号对于确定再生组织的极性（哪一端是头部，哪一端是尾部）至关重要。
• 离子通道操纵： 改变特定离子通道的活动也会产生深远的影响。 例如，改变伤口部位细胞的膜电位会影响再生的结构类型。
• 永久性生物电记忆：双头涡虫特别值得注意的是，这种特征被“锁定”了。随后的切割（例如，不使用其他药物）将再次长出两个头。 身体的“计划”已经改变，电路现在已闭合到自持模式中。
• 显示其他物种头部形状的双头涡虫：莱文和他的实验室不仅改变了头部生长的数量，还改变了其潜在的物种形状。 因此，潜在的“指令”可以持久，但仍然会有很大差异！
• 创造“无头”蠕虫： 在某些情况下，阻断间隙连接或改变离子通道可以完全阻止再生，或者导致形成无头的蠕虫。

这些实验表明，生物电不仅仅是再生的结果； 它是一个主动的调节器，控制着这个过程。 生物电模式就像一个指定身体计划的软件程序，通过操纵这个程序，研究人员可以改变再生的结果。

涡虫是研究再生的一个极好的模型系统，原因如下：

• 它们的再生能力非常出色。
• 它们是相对简单的生物体，更容易研究再生的细胞和分子机制。
• 它们易于在实验室中维护和操作。
• 它们具有特征明确的基因组。

通过研究涡虫，我们可以获得关于再生过程的基本见解，这些见解可能对人类医学产生深远的影响。 如果我们能了解涡虫如何再生整个身体，我们或许能够开发出刺激人类再生的疗法，有可能使我们重新长出失去的四肢、修复脊髓损伤或再生受损的器官。

迈克尔·莱文 生物电 101 速成课程 第九课：涡虫再生：不死蠕虫的秘密 小测验

1. 是什么让涡虫如此引人注目？

A) 它们非常大。
B) 它们可以从微小的碎片中再生出整个身体。
C) 它们会飞。
D) 它们颜色鲜艳。

2. 什么是新生细胞？

A) 一种感染涡虫的病毒。
B) 负责涡虫再生的成体干细胞。
C) 形成间隙连接的结构。
D) 构成涡虫头部的细胞。

3.涡虫新生细胞的一个关键特性是什么？

A) 它们只能变成神经细胞。
B) 它们已经完全分化。
C) 它们是多能的，能够分化成任何细胞类型。
D) 它们缺乏对生物电的反应能力。

4. 对或错：涡虫再生仅仅是伤口愈合，而不是真正的再生。

A) 对。
B) 错

5. 生物电在涡虫再生中起什么作用？

A) 没有作用。
B) 被动作用，仅仅反映遗传程序。
C) 指导作用，指导新生细胞的活动并确定身体形态。
D) 完全是破坏性的力量。

6. 什么是胚基？

A) 一种武器
B) 形成的肿瘤。
C) 在伤口部位形成的一团未分化细胞。
D) 一个开口

7. 伤口部位的生物电“图谱”告诉新生细胞什么？

A) “缺少了什么？”以及去哪里。
B) “我在哪里？”
C) “我应该变成什么？”
D) 以上都是。

8. 如果你改变/影响再生涡虫中的生物电景观会发生什么

A) 什么也不会发生，它们的 DNA 会覆盖任何和所有影响。
B) 这无关紧要，因为生物电和电压变化只发生在青蛙中，而不是蠕虫发育过程中
C) 会出现严重改变的生长和再生模式。
D) 只有新生细胞的位置会发生变化。

9. 如果你阻断再生涡虫尾部的间隙连接通讯会发生什么？

A) 它可能会像正常情况下一样重新长出尾巴
B) 它会长出内脏
C) 它可以重新长出头部而不是尾巴，形成一个双头蠕虫。
D) 什么都没有

10. 对/错 由于间隙连接被阻断而长出两个头的涡虫，保留了生物电“记忆”，此后当它繁殖时，将始终产生双头后代。

A) 正确。
B) 错误。

11. 涡虫再生研究如何可能使人类受益？

A) 它可能会导致刺激人类再生的疗法。
B) 它可以帮助我们了解如何防止衰老。
C) 它可以导致癌症的新疗法。
D) 以上都是。

12. 科学家认为再生过程是通过以下方式发生的：

A) 来自化学物质的关于身体蓝图的细胞信号
B) 生物电
C) 生物电 + 化学信息传递
D) 仅干细胞单独作用。

13. 在它受伤/被切割后，涡虫立即会发生什么？

A) 化学途径开始改变基因。
B) 什么都没有。
C) 生物电变化（只需几分钟）建立关键的新变化，以向新生细胞发出正确和适当的重建信号。
D) 几周后形成生物电模式

14. 在切割涡虫后发生的生物电变化之后会发生什么？

A) 新生细胞开始形成未分化的大量肿块。
B) 大量物质（称为“胚基”）聚集在一起以帮助重新生长缺失的组织
C) 以上都是
D) 以上都不是

15. 细胞的哪些部分协同作用来建立再生蠕虫的身体形态？

A) 离子通道、离子泵以及间隙连接之间的细胞连接性的组合作用。
B) 新生细胞。
C) 遗传指令和化学途径。
D) B 和 C

16. 哪些动物可以重新长出脑组织？

A) 蝾螈。
B) 人类
C) 老鼠。
D) 以上都是。

17. 与人类相比，哪个选项最能描述涡虫恢复身体的程度：

A) 它们像正常的“疤痕组织”一样再生。
B) 在这些情况下不会发生胚基。
C) 它完美地恢复了失去的部分。
D) 它长出 2 或 3 个身体节段，而实际上只需要 1 个。

18. 这些生物（及其近“亲”）被称为？

A) 没有特别的。
B) 具有神秘生物学的“外星人”。
C) 不朽者。
D) “时间旅行者”

19. 双头涡虫接下来可以做什么？

A) 如果让其繁殖（裂变），双头涡虫可以创造出双头系列的生物，尽管随后进行干预，它们仍将保持这种状态。
B) 如果让其自行发展（不进行繁殖），它可以自发地重新长成正常的涡虫。
C) 涡虫会变回原来的状态，并且不能存活超过一周。
D) 以上都不是。

20. 仅通过阻断间隙连接通讯，不做任何其他改变，蠕虫以前发生过什么结果？

A) 在不应该存在的地方重新长出新的肢体
B) 改变位置。
C) 创造不同的“头部形状”。
D) 以上都不是

迈克尔·莱文 生物电 101 速成课程 第九课：涡虫再生：不死蠕虫的秘密 答案表

1. B

2. B

3. C

4. B

5. C

6. C

7. D

8. C

9. C

10. A

11. D

12. C

13. C

14. C

15. A

16. A

17. C

18. C

19. A

20. C