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Can we change the blueprints of life? This week we are exploring that question with genetic engineering. We’ll discuss how selective breeding can improve agricultural practices, and the potential DNA-level engineering could have on other fields of engineering. We’ll also look at how optogenetics and CRISPR have opened up new ways for genetic engineers to change the DNA inside living cells.

Crash Course Engineering is produced in association with PBS Digital Studios: https://www.youtube.com/playlist?list=PL1mtdjDVOoOqJzeaJAV15Tq0tZ1vKj7ZV

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RESOURCES:
https://www.huffingtonpost.com/david-macaray/the-man-who-saved-a-billi_b_4099523.html?guccounter=1
http://wheatdoctor.org/lodging
https://diatoms.org/what-are-diatoms
https://www.researchgate.net/publication/49698386_From_diatoms_to_silica-based_biohybrids
https://www.pnnl.gov/news/release.aspx?id=918
https://www.vox.com/2018/7/23/17594864/crispr-cas9-gene-editing

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 Intro


Engineers like making things better. From mechanical parts to electronic circuitry: if it can be improved, somewhere an engineer is working on making it more useful to the world. Of course, the goal of all of this is to make our lives better. But there's another way in which life, in the sense of living organisms can be tailored to our benefit.

At the boundaries of engineering and scientific research, genetic engineers are working with the very blueprints of life: DNA.
By editing DNA and the genes contained within it, the field of genetic engineering is allowing us to change the nature of living beings. That can sound a little scary, and it's certainly not without its controversy. But done correctly, it could help us create more food, design new materials, treat or cure diseases, and even improve people's lives before they're born.

 Main Video


The world of genetic engineering revolves around DNA: a molecule found in nearly all the cells of most living things, which governs how those cells grow and function.

At its simplest, it consists of two, long sugar phosphate strands that spiral around one another in the famous double helix formation. And it's what links those two spirals together that determines the genetic content of DNA.

Four types of molecules called bases make up the biological code that stores information on the structure of cells and how they operate. The sequence of those bases makes up the organism's genes. And if the organism reproduces, it passes on some or all of those genes.

There's a lot of cellular machinery that goes into translating the code from DNA into the proteins that carry out different functions within a living being. But as your probably know, the end result is that different genes produce different characteristics in different living things.

Through millions of years of evolution and genetic inheritance, differences in DNA are why a tiger has stripes, but a jaguar has spots. Or why sunflowers and roses have different types of petals. And humans have been tinkering with that DNA for thousands of years - long before we even knew it existed.

The most widespread example is the food we obtain from crops. People have selectively cultivated crops and bred them to be bigger, yielding more food. That's essentially the same as picking crops with the right genes. We've also tried to make them more resilient to problems like diseases or a lack of rainfall.

As for animal DNA, we bred wolves into domesticated dogs more than 10,000 years ago. So in some ways, genetic engineering has gone on for millennia. But one of the pioneers of modern genetic engineering was American geneticist Norman Borlaug.

In 1944, Borlaug was hired by the International Maize and Wheat Improvement Center to, well, improve maize and wheat. Wheat is the third most consumed cereal crop in the world, so improving its yield would have a huge impact.

Borlaug and his team tried some traditional crop breeding techniques to make wheat more resistant to diseases like stem rust, which is caused by a fungus that shrivels the stems of plants and can even kill them. And to an extent, they were successful, but the new disease-resistant wheat plants came from wheat that had long, thin stems.

The new crops inherited those traits too which caused them to fall over which interferes with their growth and can reduce the final yields of the crops by up to 50%! So, Borlaug and his colleagues used their background in genetics to cross-breed the new wheat with a shorter Japanese variety that was more resistant to falling over -- a trait that they successfully introduced into the disease-resistant kind.

Wheat that doesn't fall over might not sound like the most amazing of accomplishments. But Borlaug's wheat was developed at just the right time to prevent a catastrophic famine from happening in India and Pakistan. In 1962, Borlaug and his fellow scientists introduced their new wheat to those countries, doubling the crop yields in the region over the next decade.

The achievement became known as the "Green Revolution." As a direct result of Borlaug's work, it's estimated about 300 million people were rescued from starvation and he was award the Nobel Peace Prize for his work in 1970. 

So genetic engineering has already changed the world for the better in significant ways. And today's techniques give genetic engineers an even more accurate and powerful toolkit for tackling other challenges.

In addition to addressing food shortages, we could tweak the development of certain plants for the production of biofuels, like ethanol derived from corn or genetically engineered algae.

In fact, algae can be engineered to produce more than just fuel. If we can edit the right genes, we could create large amounts of what are known as diatoms. Diatoms are special forms of algae with cell walls made of silica. They're literally living in glass houses. That special property gives diatoms lots of applications in nano-engineering. They can be arranged onto surfaces to produce biosensors, used to detect explosives, or sent to deliver drugs inside the body.

Genetic engineering could help synthesize and manipulate diatoms more efficiently. And the medical benefits aren't limited to delivering drugs -- genetic engineering could also be used to produce medications in the first place.

Certain kinds of bacteria produce enzymes (proteins that speed up chemical processes) which can, in turn, produce the chemicals used in pharmaceutical drugs. For example, the enzyme P450 is used to create drugs for cancer treatment, but it's naturally produced by plants.

By inserting the genes of a P450-producing plant into bacteria, researchers can create factories of genetically engineered bacteria that generate P450 in greater amounts.
This type of strategy can make the drug production process much more efficient - a similar method is already used to produce insulin, for example. Even better than treating diseases would be stopping them from happening in the first place. 

Which brings us to one of the more controversial uses of genetic engineering: genetic treatments for unborn animals, including humans.

Certain diseases are caused by issues in an organism's DNA. Mutations happen when there's a glitch in the DNA-copying process and the base pairs in the gene aren't transcribed perfectly. 

In humans, for example, mutations can lead to heart conditions like hypertrophic cardiomyopathy, which thickens some of the muscle in the heart, stopping it from pumping blood efficiently and forcing the heart to work harder.

If we could edit the DNA in an embryo to fix a mutation or delete a carrier gene for a disease, it would prevent the disease from being there when the person was born and grew up. On a genetic level, it's like removing and entire disease.

Of course, many are concerned that genetic engineering would be used to modify humans for other traits, from the color of their hair and eyes to their intelligence. And whether or not that's something we want to do as a species is still being debated. But modern methods are far from delivering that kind of control, while certain diseases are already being tackled with current techniques.

So genetic engineering has an enormous amount of potential. But the real challenge comes from how we actually chop and change genes. There are few different ways geneticists do this, but two breakthrough techniques have blown the doors open in genetic engineering over the last decade: optogenetics and CRISPR.

Optogenetics involves modifying cells to make them sensitive to light - brain cells, for example.

Understanding the human brain is an enormous challenge, one that the National Academy of Engineering in the US has made one of their Grand Challenges for the 21st Century. And one of the major obstacles is that we still don't know exactly what each cell in the brain does.

Since the human brain has certain structures similar to those in other animals - especially mammals - studying the brains of those animals can help build a better model of our own.
Essentially we need to be able to turn individual brain cells on and off and see how that affects an animal's behavior to help understand how neurons work together throughout the body. Changing the variables and measuring the outcomes - that's the heart of scientific testing.

Brain cells have certain proteins on their surfaces called ion channel receptors, which are chemical channels into the cells that act like switches. They activate or deactivate brain cells when a chemical, like a neurotransmitter, hits them.

Here's where it gets clever. Viruses are usually bad news for the organisms they're being hosted in. Certain viruses can attack a cell's DNA and insert rogue bits of genetic code, making the cells malfunction. But because some viruses can introduce DNA to cells, they can also be put to good use for genetic engineering purposes.

For example, viruses modified to carry certain bits of DNA can give a cell light sensitive proteins, called opsins, embedded in its ion channel receptors. Do that to brain cells in, say, a rat and you can turn those cells on and off by beaming pulses of light directly to the cell using fiber optic cables.

Researchers have already used this technique to study the motion circuits in the brains of mice, even controlling their motion. They've also manipulated cells that govern sleep in fruit flies, waking them up and putting them to sleep with flashes of slight.

Both the motor cortex in mice and the sleep cycle in fruit flies have parallel structures in humans, so optogenetics offers a powerful way to model human brain physiology.

Another star genetic engineering technique uses chunks of bacterial DNA called Clustered Regularly Interspaced Short Palindromic Repeats. To avoid that mouthful, the technique is referred to simply as CRISPR editing.

CRISPR can edit DNA in a way that's easier to customize, and can both remove particular genes from a cell and add new ones. It relies on a defense mechanism found in bacteria to defend against viruses.

Bacteria like E. coli produce certain proteins that fight off viruses attacking the cell. When they succeed in fighting off the invaders enzymes in the cell actually take parts of the virus DNA and store it within the cell.

If another virus attacks later on, the bacteria produce special attack enzymes, known as Cas9, that carry around those stored bits of viral genetic code like a mug shot. When Cas9 enzymes come across a virus, they see if they virus contains the genetic information that matches the mug shot. If it's a match, the Cas9 enzyme chops up the virus's DNA to neutralize the threat.

These mechanisms are exactly what genetic engineers need: the ability to store and recognize portions of genetic code on a microbiological level, and to cut DNA and add parts of it where needed.

So with CRISPR-Cas9, genetic engineers have an incredibly versatile toolkit for editing genes in living beings. So among other things, CRISPR could help cure disease like cancer, sickle cell disease, and certain kinds of muscular dystrophy.

In theory, all you have to do is remove the mutations and put in the correct, healthy DNA sequence. There are lots of other approaches genetic engineers can use too, but CRISPR is one of the most popular ones being used in research right now.

Still, CRISPR is far from perfect in its current form. Changing DNA isn't consequence-free and if done incorrectly, it can even cause the very genetic diseases and mutations researchers want to cure.

SO there's a long way to go before we're fully genetically engineering humans on the DNA level. But in the future, techniques like these may lead to cures for all kinds of diseases and, like so many fields of engineering, improve a lot of people's quality of life. 

In this episode we looked at genetic engineering. We saw that DNA was the underlying mechanism for how genes are inherited by living things and how it determines and organism's features.

We saw how selective breeding can improve agricultural practices and the potential DNA-level engineering could have on other fields of engineering.

Finally, we saw how optogenetics and CRISPR have opened up new ways for genetic engineers to change the DNA inside living cells.

In our next episode we're going to be combining too awesome things: food and engineering.

 Outro


Crash Course Engineering is produced in association with PBS Digital Studios, which also produces Deep Look, a show that explores big scientific mysteries by going very, very small. 

See the unseen at the very edge of our visible world, from eye popping mantis shrimp to blood sucking mosquitoes. Check it out at the link in the description.

Crash Course is a Complexly production and this episode was filmed in teh Doctor Cheryl C. Kinney Studio with the help of these wonderful people and our amazing graphics team is Thought Cafe.