How to give snakes their legs back

Also, why some people have more fingers than others. And can the planet actually support 8 billion people?

8 billion.

That’s the number of people on the planet right now. Is it too many people? How many more people can the world support?

There are no easy answers. Usually experts and public intellectuals who are asking and answering these questions approach them from demographics or developmental economics. They focus on technological advances in production that allow more humans to live and prosper.

But humans are not the only species on the planet, we share this home with myriad lifeforms. It is undeniable that the growth of human population in the last century has had a catastrophic impact on the natural environment (or what’s left of it). We are undergoing a mass extinction event. We are causing climate change. We are cutting down forests and choking the oceans with plastic.

The question we should also ask is if there should be more people on the planet. And if we want to increase the lifespan and prospects for everyone on the planet while sustaining the environment as a home for others species, then the answer to the question is loud and clear.

---

Evolution is everywhere in biology and it is the lens through which we understand life.

Online there’s a ton discussion of the “invisible hand” as a force, but not often a discussion of the invisible force that gave rise to the actual hand - evolution.

This week I want to talk about the specific case of how hands and legs are related across different animals.

Snake ancestors once had legs. And there’s a way for them to get legs back.

This section is modified from a column I wrote for Hindustan Times a few months ago.

One of the remarkable aspects of biology is just how much of our genes are shared with other animals. A flavor of the same gene that helps build a fly also makes a person.

Fruit flies are found in genetics labs all around the world because they are easy to work with and have many of the same genes that are involved in the development of more complex animals like humans.

In the 1980s, biologists Christiane Nüsslein-Volhard and Eric Wieschaus found many of the genes responsible for the development of flies. Amazingly, these genes also have similar and vital roles in other animals including humans. For their discovery, they shared the 1995 Nobel Prize in Physiology or Medicine.

One mutation in a fruit fly gene that causes the fly embryo to look stumpy was named hedgehog. Soon, multiple versions of the gene were found and named Desert Hedgehog and Indian Hedgehog. At the time, the third gene was discovered, Sega’s game Sonic the Hedgehog was popular. Robert Riddle, the discoverer, whimsically named it Sonic Hedgehog.

Since its discovery in flies, Sonic Hedgehog has been found in a wide array of animals. In humans, the gene is known as SHH. It gives rise to an incredibly powerful protein that diffuses out of cells and synchronizes the development of vertebra, lungs, brain, limbs, and organs. 

Don’t be taken in by the facetious name: Sonic Hedgehog can make a fish look like a fish, and a human look like a human.

For animals that fly, swim, or walk there’s a genetic circuit that determines our limb patterns. Although the functions of a leg, fin, or wing are different, quite astoundingly the same circuit has been preserved for hundreds of millions of years across different species. If Sonic Hedgehog is activated in the right way at the right time, then we get a fully formed animal that looks like it’s supposed to. 

On the other hand, the complete loss of Sonic Hedgehog can cause a major defect in which two eyes merge to become one. This “cyclops” condition has been found in offspring of sheep that ingest a weed containing a chemical called cyclopamine. Fortunately, this fatal condition is rare in newborn humans.  

The same genetic switch that causes snakes to not have legs is changed in some people to give them extra toes and fingers. 

In more recent years, we’ve learned that Sonic Hedgehog works in tandem with another DNA sequence which is its enhancer. The enhancer turns on Sonic Hedgehog when it is supposed to be turned on, and it causes birds to have wings, fish to have fins, and humans to have fingers.  Like a puppeteer moving the strings of a puppet, the enhancer controls Sonic Hedgehog. 

What is really surprising is that the enhancer is found at a long-distance (close to a million letters away in DNA) from Sonic Hedgehog, the gene it controls. This is like finding a light in your bedroom is turned on by a dial in a house in a different city. 

The enhancer is like a rheostat that can increase or decrease the amount of Sonic Hedgehog.

A single letter change in its DNA sequence can result in an extra toe or finger in a person.

This condition, known as polydactyly, has also been seen in mice, cats, and guinea pigs. A much greater change in the enhancer can result in loss of limbs.  In fact, it is the enhancer that causes the shape of snakes.

A polydactyl cat (Image via Wikipedia)

One of the defining characteristics of snakes is, of course, that they have no legs. Some snakes like cobras and vipers are completely limbless. Others like pythons and boas have, hidden away, remnants of legs like pelvic girdles and parts of the femur. 

Around 150 million years ago, the ancestors of snakes did have functioning legs. Researchers have even found snake fossils that are 90 million years old with working hind limbs. 

Snakes lost their legs due to mutations in the enhancer of Sonic Hedgehog.  But we know that snakes didn’t lose their legs all at once.

Researchers have found that the effect of the snake enhancer reduced over time, causing ancestors of modern snakes to have progressively shorter and shorter legs. 

The evolution of snakes involved monumental changes to the standard lizard body plan. And it wasn’t exactly a clear path to “leglessness” either. Some snake families probably lost and regained legs over millions of years. 

Can we make other animals more snakelike in shape?

Mice are standard lab animals for genetic experiments. So these experiments have been done in mice.

• If we genetically modify mice with enhancer sequences from other limbed animals like humans or fish, they keep their limbs.

• If we insert enhancer sequences from pythons (which have rudimentary limbs), there’s some limb development.

• But if we take the enhancer sequence of a completely limbless snake like a cobra and put it into mice, it creates stunted mice.

Put a snake’s genetic unit in a mouse, and the mouse starts to look a little bit more like a snake.

What about the other way around?

Can we insert enhancer sequences (from mice or humans) into snakes and give them legs?

The idea of limbed snakes might be alarming to you know, but as I mentioned, snake ancestors did have legs which they lost over millions of years.

Once the enhancer that gives rise to legs was finally lost in snakes, it probably caused a domino effect in the loss of other genes needed for legs to be formed. So, turning legs back on in snakes will be harder than creating a limbless animal. 

But since evolution has created them in the past, legged snakes are in the realm of possibility. 

---

That’s it for this week. If you enjoyed my newsletter, please share, like, or leave a comment below.

I’m no longer on Twitter. You can find my science posts on mastodon @anirban@fediscience.org and my other stuff at @anirbanM@mastodon.social.