Page 6 - Science Focus (Issue 19)

因為 Shh 是一種分級的（graded）訊號，意味著細胞暴露於
CYCLOPAMINE AND
THE ONE-EYED SHEEP
By Kit Kan 簡迎曦
ᐑˋᶶ ఊ଻ၧϺ
ၾ
Most people consider one-eyed creatures like
Mike Wazowski from the movie Monster Inc. and the
cyclopes in Greek mythology to be fictional, because
they have never seen animals like that in real life.
Therefore, when sheep in the western United States
gave birth to one-eyed lambs in the 1950s, the sheep
ranchers freaked out. After decades of research,
scientists finally identified the culprit that caused the
disease and the underlying mechanism.
The singular eye deformity is caused by a
compound called cyclopamine, which can be found
in the plant Veratrum californicum. Ingestion of the
plant at a certain stage during pregnancy hinders
the development of the embryo – preventing the
primitive, single “eye structure” from developing into
two separate eyes, hence giving rise to only one eye.
But how does a single molecule, cyclopamine, cause
such great developmental changes? It all begins with
a protein called sonic hedgehog.
Sonic Hedgehog and Cycloptic Sheep
The sonic hedgehog protein (Shh) is encoded by
the SHH gene and plays an essential role in embryonic
development. Shh binds to a receptor on the cell
membrane called Patched to inhibit it. Since Patched
normally inhibits another protein named Smoothened,
when Patched is inhibited by Shh, Smoothened is
activated (double negative), which could lead to
the expression of certain genes. The sonic hedgehog
signaling is more complicated than that since it is
a graded signaling pathway, meaning that cells
exposed to different concentrations of the Shh respond
in different ways, and will eventually differentiate into
different tissues. In the early stages of development,
there is a single structure called the eye field, which
gives rise to two distinct eyes in the later stages
with the help of the concentration gradient of Shh.
Likewise, the left and right hemispheres of the brain
are formed involving the same mechanism. Shh is not
just responsible for the brain and eye development,
but also the tooth, limb, and lung development.
Cyclopamine is an inhibitor of the sonic hedgehog
signaling pathway. It has a very high affinity to
Smoothened, binding it tightly and inhibiting it.
Thus, even when Shh binds and inhibits Patched,
Smoothened cannot execute its normal function of
inducing gene expression [1]. If an ewe ingests the
toxic plant and expose the embryo to cyclopamine
at around day 14 of gestation [2], the brain and the
eye field of the embryo will not separate, resulting in
the deformity [3]. As mentioned previously, since the
proper division of the two hemispheres of the brain
also requires Shh protein [3], the cycloptic sheep not
only has a deformed face, but also a deformed brain,
which is why cyclopamine poisoning is potentially fatal.
From Fatal Poison to Cancer Therapy
The sonic hedgehog signaling pathway is
also critical at later stages in life after embryonic
development. Smoothened is a proto-oncogene while
Patched is a tumor-suppressor gene. Tumor-suppressor
genes, as the name implies, suppress the growth of
tumor; and proto-oncogenes, when mutated, could
contribute to the development of cancer. Basal cell
carcinoma, the most common type of skin cancer,
and medulloblastoma, the most common type of
primary brain cancer in children, are some cancer
types that result from mutations that over-activate
不同濃度的 Shh下會有不同的反應，最終會分化為不同的組
織。在胚胎發育的早期階段，只有一個稱為視場（eye field）
的單一結構，該結構會在後期借助 Shh 的特定濃度發展出
兩隻獨立的眼睛。同樣，大腦左右半球的形成亦涉及相同的
原理。Shh 不僅負責大腦和眼睛的發育，而且還負責牙齒，
四肢和肺部的發育。
環巴 胺 是 Shh 訊 息 傳 遞 路 徑 的 抑 制 劑，它 能 夠 與
Smoothened 緊密結合並抑制它。因此，即使 Shh 結合並
抑制 Patched，Smoothened 也無法發揮其誘導基因表達
的正常功能 [1]。如果母羊於妊娠的第 14 天左右攝入了帶毒
性的加州藜蘆 [2]，令胚胎接觸到環巴胺，胚胎的大腦和視
場便不會分化成左右兩邊，從而導致畸形的情況 [3]。如前
所述，由於大腦兩個半球的適當劃分亦需要 Shh 蛋白 [3]，
Smoothened or inactivate Patched [4]. To deal with it, 因此單眼綿羊不僅臉部變形，大腦也會變形，這就是環巴胺
中毒有可能致命的原因。
agents which can inhibit the activity of Smoothened
(or Smoothened inhibitors) can potentially be used as ੽ߧնݭᖹՑᐖसطᐕ
drugs to slower cancer progression. Going from a fatal
poison to a cancer therapy sounds too good to be Shh 訊息傳遞路徑在胚胎發育以後的人生階段也很關
true – although the cyclopamine derivative, saridegib, 鍵。Smoothened 是 原 癌 基 因（proto-oncogene），而
failed the clinical trial due to its unsatisfactory efficacy Patched 是腫瘤抑制基因（tumor-suppressor gene）。
[5], it has inspired the birth of the two FDA-approved 顧名思義，腫瘤抑制基因可以抑制腫瘤的生長；而原癌基因
drugs, vismodegib and sonidegib, which are also 在突變後，則可能有利於癌症的發展。基底細胞癌是最常見
Smoothened inhibitors [2]! 的皮膚癌類型，而髓母細胞瘤是兒童中最常見的原發性腦癌
While you try to get the disturbing picture of the 類型，這兩種癌症是一些因 Smoothened 和 Patched 突變
cycloptic sheep out of your mind, try to appreciate 而可能形成的癌症種類，當中通常是突變使 Smoothened 過
how innovative and creative scientists are, that they 度激活或使 Patched 失活 [4]。為解決這個問題，使用抑制
literally turn poison into medicine!
Smoothened 活性的藥物（即 Smoothened 抑制劑）有可
能減緩癌症進展。從致命毒藥變成癌症療法聽起來太不可思
大多數人認為像電影《怪獸公司》中的「大眼仔」米高•華素 議 — 儘管環巴胺衍生物 saridegib 因療效欠佳而未能通過
基（Mike Wazowski）和希臘神話中的獨眼巨人這樣的單
眼怪物都是虛構的，因為我們在現實生活中從未見過像這樣 臨床試驗 [5]，但它啟發了兩種 FDA 批准的藥物 vismodegib
的生物。因此，當在 1950 年代美國西部有綿羊生下獨眼羔 和sonidegib 的誕生（它們也是 Smoothened 抑制劑） [2]！
羊時，牧場的主人們都給嚇壞了。經過數十年的研究，科學家
終於確定了導致該疾病的罪魁禍首及背後的生物學原理。 當你試圖從腦海中刪除那令人不安的單眼綿羊畫面時，也
可嘗試欣賞科學家的創新精神和創意，因為他們確實將毒藥
這種畸形單眼的現象是由一種名為環巴胺（cyclopamine） 變成了抗癌藥物！
的化 合 物 引 起 的，這 種 化 合 物 可 以 在 植 物 加 州 藜 蘆
（ Veratrum californicum）中找到。在懷孕期間的某個階 References 參考資料：
段攝入加州藜蘆會阻礙胚胎的發育，它阻止原始單一的眼睛 [1] Chen JK, Taipale J, Cooper MK, Beachy PA. Inhibition of
結構分化成兩隻獨立的眼睛，從而只產生一隻眼睛。可是，環 Hedgehog signaling by direct binding of cyclopamine to
Smoothened. Genes Dev. 2002;16(21):2743-2748. doi:10.1101/
巴胺究竟是如何引起如此巨大的發育變化呢？這一切都始於 gad.1025302
一種叫做音速刺蝟（Sonic hedgehog/Shh）的蛋白質。 [2] Chen JK. I only have eye for ewe: the discovery of cyclopamine
and development of Hedgehog pathway-targeting drugs. Nat
Prod Rep. 2016;33(5):595-601. doi:10.1039/c5np00153f
[3] National Library of Medicine. SHH gene. Genetics Home
ࠪ஺Ր㾲ձఊ଻ၧϺ Reference. Updated September, 2010. https://ghr.nlm.nih.gov/
gene/SHH#sourcesforpage.
音速刺蝟蛋白（Shh）由 SHH 基因編碼而成，在胚胎發 [4] Taipale J, Chen JK, Cooper MK, et al. Effects of oncogenic
育中扮演相當重要的角色。Shh 會與在細胞膜上的稱為 mutations in Smoothened and Patched can be reversed
Patched 的受體結合並抑制它。由於 Patched 通常會抑 by cyclopamine. Nature. 2000;406(6799):1005-1009.
doi:10.1038/35023008
制另一 種 名 為 Smoothened 的 蛋 白，因 此 當 Shh 抑 制 [5] Levin J. Infinity Stops Phase 2 Trials of Saridegib in
Patched 時，Smoothened 會被激活（雙重否定），這能引 Chondrosarcoma and Myelofibrosis. Fierce Biotech. Updated
June 18, 2012. https://www.fiercebiotech.com/biotech/infinity-
stops-phase-2-trials-of-saridegib-chondrosarcoma-and-
發某些基因的表達。但 Shh 的訊息傳導並不是非黑即白的， myelofibrosis.