In the 1950s, ranchers in Idaho were baffled when their sheep started giving birth to lambs with a peculiar deformity: they had only one eye, resembling the mythical cyclops. Seeking answers, the ranchers enlisted the help of scientists from the U.S. Department of Agriculture. The researchers suspected that the sheep had eaten poisonous plants that caused these birth defects. To test this theory, they collected local plants and fed them to lab rats, but they couldn’t reproduce the same effect. Determined to solve the mystery, one scientist even lived with the sheep for three summers to observe them closely.
After a decade of investigation, the scientists finally pinpointed the cause: wild corn lilies. These plants contained a molecule with six connected rings, which they named cyclopamine, inspired by the cyclops-like appearance of the lambs. Although the researchers didn’t fully understand how cyclopamine caused the deformity, they advised ranchers to keep their sheep away from these plants.
It wasn’t until about forty years later that a team of biologists, led by Professor Philip Beachy, uncovered the mechanism behind this phenomenon. Beachy’s lab was studying a gene known as the hedgehog gene, found in many species, including mice and humans. This gene got its name from two scientists who discovered that mutating it in fruit flies resulted in spiky features resembling a hedgehog. Beachy and his team experimented by deactivating the hedgehog genes in mice, which led to severe developmental defects in their brains, organs, and eyes. While reading a textbook, Beachy stumbled upon photos of the cyclops sheep and realized that the hedgehog gene might be involved.
Genes are like instruction manuals for cells, telling them what to do and when. They communicate these instructions through proteins. The hedgehog gene directs cells to produce a protein called the hedgehog protein, which starts a complex chain of signals. In normal development, the hedgehog protein binds to another protein called patched, which then allows a third protein, smoothened, to send signals that guide cells on where to go and what to become. Cyclopamine, found in corn lilies, disrupts this process by binding to smoothened, preventing it from sending the necessary signals. This interference stops the brain from developing into two hemispheres and affects the formation of distinct fingers and eyes.
While this discovery explained the cyclops sheep, Beachy and his team also saw a potential medical application. They noticed that uncontrolled activation of the smoothened protein was linked to Basal Cell Nevus Syndrome, a condition that increases the risk of certain cancers. The scientists proposed using cyclopamine’s ability to bind to smoothened as a cancer treatment, provided the patient wasn’t pregnant. However, cyclopamine had side effects and was difficult to work with. Fortunately, researchers found related molecules that were safe and effective, leading to the approval of two skin cancer drugs in 2012 and 2015.
What began as a puzzling case of cyclops sheep turned into a significant medical breakthrough, illustrating that sometimes, a deeper investigation can lead to unexpected and valuable discoveries.
Investigate other plants known to cause birth defects in animals or humans. Prepare a presentation that discusses the plant, its active compounds, and the mechanism by which it causes deformities. Share your findings with the class to enhance understanding of teratogenic effects in nature.
Analyze the case of cyclopamine and its impact on the hedgehog signaling pathway. Write a report detailing how cyclopamine disrupts normal development and its implications for both the cyclops sheep and potential medical applications. Discuss the ethical considerations of using such compounds in medicine.
Participate in a workshop where you will model the hedgehog signaling pathway using interactive tools or software. Work in groups to simulate how different molecules interact within the pathway and predict the outcomes of various disruptions, such as those caused by cyclopamine.
Engage in a debate on the pros and cons of using natural compounds like cyclopamine in developing medical treatments. Consider aspects such as safety, efficacy, ethical concerns, and the potential for new drug discoveries. Prepare arguments and counterarguments to present in class.
Visit a local botanical garden to learn about various plants, including those with medicinal properties or toxic effects. Document your observations and relate them to the concepts discussed in the article. Reflect on how plant compounds can influence both health and disease.
In the 1950s, a group of ranchers in Idaho were puzzled when their sheep gave birth to lambs with a unique deformity. Confounded by these cyclops sheep, they called in scientists from the U.S. Department of Agriculture to investigate. The researchers hypothesized that the pregnant ewes had consumed poisonous plants that could cause birth defects. They collected local flora and fed samples to lab rats but struggled to replicate the effect. Consequently, they decided to directly observe the sheep, with one scientist even living with the herd for three summers. After a decade of trial and error, the scientists finally identified the culprit: wild corn lilies. The lilies contained an active molecule with six connected rings, which they named cyclopamine in reference to the cyclops sheep. While they didn’t fully understand how cyclopamine caused the defect, they advised ranchers to avoid the plants.
It took about four decades before a team of biologists, led by Professor Philip Beachy, discovered the underlying mechanism. His lab was studying a specific gene found in many species, from mice to humans, known as the hedgehog gene. This gene was named by two scientists who later shared the Nobel Prize for their work, as they found that mutating this gene in fruit flies produced pointy spikes resembling a hedgehog. Beachy and his colleagues performed genetic modifications to deactivate the hedgehog genes in mice, resulting in severe defects in the development of their brains, organs, and eyes. While reviewing a textbook, Beachy came across photos of the cyclops sheep and realized what had eluded scientists for decades: something must have gone wrong involving the hedgehog gene.
To explain further, genes contain instructions that tell cells what to do and when to do it, communicating their directives through proteins. The hedgehog gene instructs cells to release a protein called hedgehog protein, which initiates a complex series of cellular signals. In normal healthy development, the hedgehog protein binds to another protein called patched, which inhibits patched and allows a third protein called smoothened to signal the cells, directing them on where to go and what types of tissues to become. Cyclopamine, found in corn lilies, disrupts this pathway by binding to smoothened, preventing it from sending the necessary signals to properly develop the brain into two hemispheres and to form distinct fingers and eyes.
This clarified the science behind the one-eyed sheep, but Beachy and his team also recognized a potential beneficial connection. They noted that uncontrolled activation of the smoothened protein was linked to a human syndrome known as Basal Cell Nevus Syndrome, which predisposes individuals to certain cancers. The scientists proposed utilizing cyclopamine’s ability to bind to smoothened as a treatment for these cancers, provided the patient was not pregnant. Unfortunately, researchers later discovered that cyclopamine has negative side effects and its chemical properties make it challenging to work with. However, they did find that closely related molecules are safe and effective, leading to the approval of two of these drugs as skin cancer treatments in 2012 and 2015.
When those farmers first encountered the cyclops sheep, they could have dismissed it as a random genetic mutation. Instead, their decision to investigate transformed a mystery into a medical breakthrough, demonstrating that sometimes there is more than meets the eye.
Cyclops – A genetic mutation resulting in a single eye located in the center of the forehead, often used in developmental biology studies to understand craniofacial abnormalities. – In the study of vertebrate embryogenesis, the cyclops mutation provides insights into the molecular pathways that regulate eye development.
Sheep – A domesticated ruminant mammal often used as a model organism in genetic research due to its similarities to human physiology and genetics. – Researchers utilized sheep to study the effects of gene editing on wool growth and quality.
Gene – A segment of DNA that contains the necessary information to produce a functional product, typically a protein, and is the basic unit of heredity. – The BRCA1 gene is crucial in maintaining genomic stability and preventing breast cancer.
Hedgehog – A signaling pathway that plays a critical role in regulating embryonic development and cell differentiation. – Mutations in the hedgehog signaling pathway can lead to developmental disorders and contribute to the formation of tumors.
Protein – A large, complex molecule composed of amino acids that performs a variety of functions in the body, including catalyzing metabolic reactions and supporting cellular structure. – The p53 protein is known as the “guardian of the genome” due to its role in preventing cancerous growth.
Smoothened – A protein that transmits signals in the hedgehog signaling pathway, playing a crucial role in the regulation of cell growth and differentiation. – Inhibitors of the smoothened protein are being explored as potential treatments for basal cell carcinoma.
Development – The process by which organisms grow and develop, involving a series of regulated genetic and cellular events. – The study of limb development in vertebrates has provided significant insights into evolutionary biology.
Cancer – A disease characterized by uncontrolled cell division and the potential to invade or spread to other parts of the body. – Understanding the genetic mutations that lead to cancer is essential for developing targeted therapies.
Plants – Multicellular organisms in the kingdom Plantae that use photosynthesis to produce energy and are often studied for their genetic diversity and adaptability. – Genetic engineering in plants has led to the development of crops with improved resistance to pests and environmental stresses.
Defects – Abnormalities or malformations in an organism, often resulting from genetic mutations or environmental factors during development. – Researchers are investigating the genetic basis of congenital heart defects to improve early diagnosis and treatment.
