Frankenstein Can’t Come Out And Play Today

In the standard Frankenstein story, a scientist creates an unnatural monster that breaks out of the lab and runs amok. But why should unnatural make something unstoppable? The contrary is possible, too. Imagine a different story: Frankenstein’s monster escapes, realizes that it can’t survive in the outside world, and retreats back to the lab. This story line may not make for a satisfying movie, but it might be a good goal for real life.

The fear of the unstoppable unnatural has been with us ever since scientists began moving genes between species in the 1970s. In a 1973 experiment, researchers transferred a gene from a frog into Escherichia coli. The gut microbe used the frog gene to make a frog protein.

It wasn’t long before researchers figured out how to use genetic engineering to turn microbes into factories. When scientists inserted the gene for human insulin into E. coli, the bacteria were able to manufacture a drug that had previously been harvested from cow pancreases. E. coli became the workhorse of biotechnology, spewing out drugs, vitamins, and industrial materials. (For more on E. coli’s strange yet significant history, see my book Microcosm.)

At first, the prospect of foreign genes in E. coli was terrifying. Some critics warned that insulin-producing bacteria would escape from fermenting tanks, get into people’s bodies, and cause an epidemic of diabetic comas. That never happened, probably because insulin does E. coli no good at all. The human gene is a burden to the microbe, draining off energy and resources it could use to grow.

Nevertheless, it was conceivable that some other creation might turn out to be dangerous. The scientific community responded by laying down guidelines for working with genetically engineered creatures. Most of the guidelines involved creating physical barriers to keep organisms from escaping factories or labs. But scientists have also created biological barriers, by changing the creatures themselves to make it hard for them to survive outside the lab.

For example, scientists who study the plague engineered a safe strain of the bacteria Yersinia pestis that they could work with in their labs. Y. pestis needs iron to survive, and it uses special molecules to scavenge the element from our bodies. To make a safe strain, scientists shut down some of the iron-scavenging genes in the bacteria. The bacteria could still grow in a flask if they got a rich supply of iron. But inside people, where iron is scarce, they would starve.

At least that was the plan. In 2009, a University of Chicago scientist named Malcolm Casabadan got infected by a lab strain of Y. pestis and died of the plague. Unfortunately, neither he nor anyone else knew that he suffered from a genetic disorder called hemochromatosis, which caused him to accumulate high levels of iron in his blood. Investigators concluded that his body probably served the same role as an iron-rich lab flask. Inside him, the hobbled bacteria could grow.

Casabadan didn’t die because the engineered Y. pestis that infected him was unnatural. The problem was that it wasn’t unnatural enough. That is, it could still find a place in the natural world where it could thrive. Some scientists think a better safeguard would be to create life that is fundamentally unnatural–in other words, that cannot possibly survive without our help, because the natural world is alien to it.

Fortunately, this goal does not require scientists to create an utterly alien form of life, complete with some alternate form of heredity to take the place of DNA. Scientists can take advantage of the fact that all living things on Earth are incredibly similar, chemically speaking.

All living things build proteins from about twenty building blocks, called amino acids. By combining the amino acids in different sequences, life can produce a vast range of proteins. But there are hundreds of other kinds of amino acids in nature, and scientists have created many others that are never found in nature.

In theory, living things should be able to use these amino acids to build their proteins, too. They don’t, however, because all living things share a nearly identical code for translating the information in their genes into proteins.

Genes are made of a different set of building blocks, called bases. To build a protein, a cell reads three bases at a time (a codon) and then selects a corresponding amino acid. If a base called guanine appears three times in a row in a gene, for example, a cell will pick out an amino acid called glycine.

For the most part, all living things rely on the same genetic code. That’s why E. coli that acquires a human insulin gene makes insulin, too, instead of collagen or hemoglobin. It’s also why viruses can invade our bodies and use their own genes and proteins to hijack our cells to make new viruses. We all use the same language, and so our programming can be hacked.

About a decade ago, Farren Isaacs, then a postdoctoral researcher in the lab of George Church at Harvard, started tinkering with the genetic code, trying to change the rules. Last year, he and his colleagues reported that they had reassigned one codon in E. coli to an artificial amino acid. (It’s known as p-acetyl-L-phenylalanine, or pAcF for short.) They sprinkled the new codon across the genome of the bacteria, which then made some of its proteins using pAcF.

The recoding had a remarkable effect on the bacteria: they became immune to a virus that specializes on infecting E. coli. By changing the code, the scientists made the bacteria harder to hack. (I wrote about this work in more detail in 2013 in Nautilus.)

While these bacteria could make unnatural proteins, they didn’t depend on the proteins for survival. Growing on a regular diet of natural compounds, they could still thrive. Isaacs went on to Yale, where he continued his research, as have Church and his colleagues at Harvard. And in Nature, each team has now published the next logical experiment in this line of research. Each group has recoded E. coli so that it now depends on an artificial amino acid. Without it, the bacteria cannot build essential proteins, and they die.

Because these bacteria can’t find these artificial amino acids in the outside world, the scientists reasoned that they couldn’t survive on their own. To test that possibility, they transferred the recoded microbes to dishes where they got an ordinary diet. In all but one trial, the scientists found no evidence of the recoded bacteria surviving without their essential amino acid. And in the one trial where they did survive, they barely clung to life, easily outcompeted by ordinary E. coli.

To further reduce the odds of the bacteria surviving on their own, the researchers are now building in other features. Church’s group, for example, is reassigning other codons to other unnatural amino acids, further reducing the odds even more that mutations can rescue the bacteria. Ultimately, they hope to push these creatures into an alternate biological universe, walled off from our own.

What could we do with such creatures? We could potentially use them not just in protected labs, but in the outside world. They might clean up oil spills, for example, surviving as long as we supplied the artificial amino acids they needed to build proteins. When their job was done, we could shut off the supply and they’d die. It’s conceivable that scientists could recode plants as well, creating crops that could only grow with our help.

When I talked to other experts about this research, they were pretty impressed. “It’s a landmark moment,” Tom Ellis of Imperial College told me. “I think that it will have an immediate positive impact,” said Karmella Haynes of Arizona State University.

But when I talked to bioethicist Paul Wolpe of Emory University, he thought it unlikely that we’re home-free when it comes to risks from genetic engineering. In the past, people have introduced animal and plant species to new places with the best of intentions, only to see them cause unanticipated harm. “While I applaud these first steps, caution should be the guide here,” Wolpe said.

I expect that most of the conversations these odd bugs will inspire will be about practical matters–about making valuable stuff and avoiding risks to our health. But this research speaks to something deeper. When we try to figure out the definition of life, we look around at the life we know and look for the features all living things have in common. But scientists have also wondered if life as we know it may take up a tiny portion of the space of all possible forms that life can take.

These altered bacteria tell us that suspicion is likely true. With a few years’ work, they’ve made creatures that are probably unlike anything that ever lived on Earth. And within their universe–the universe of artificial amino acids that exists in Massachusetts, Connecticut, and a few other places on Earth–they are as alive as we are.

8 thoughts on “Frankenstein Can’t Come Out And Play Today

  1. most of the time, bacteria reproduce asexually. in the process of conjugation, what is stopping a recoded bacteria from receiving the DNA required for it to grow in a natural environment from a ‘normal’ E. coli?

    [CZ: The way Church explains it, the unnatural amino acids are incorporated into a lot of proteins. The only way to swap them out with genes for “all-nature” proteins would involve gigantic chunks of the E. coli genome–which means also kicking out all the genes for the special jobs you want the bacteria to do. So even if this could happen–incredibly unlikely–it would just turn the bacteria into plain old E. coli.]

  2. Remember Jurassic Park. Nature will find a way! DNA has found a way to exist in the most extreme places and situations.

  3. Following up on Caroline: say an altered E coli has a gene that we want expressed but don’t want to get in the wild, so it also has these artificial amino acids genes. That E coli conjugates with a normal E coli, and the normal E coli only picks up the one gene we don’t want to get in the wild. Is something like that possible?

    It doesn’t mean this is a bad idea, I’m just trying to understand whether mutation is the only path around the safeguard.

  4. “Life finds a way,” says the ghost of Ian Malcolm from Jurassic Park… far more true for bacteria than for fictional dinosaurs.

  5. “The recoding had a remarkable effect on the bacteria: they became immune to a virus that specializes on infecting E. coli.”

    Many education systems fuss over the use of immune vs resistant, and usually the use of either word is pretty clear cut. In the case above I am not sure, but from my own background in microbiology I would lean toward describing E.coli as becomming resistant to the virus – immunity usally implies a response with antibodies and white blood cells.

  6. Risks & benefits from genetic engineering need to be examine closely. Manipulation of the natural environment have already create havoc for many native plants and animals leading to their extinction. Can you imagine the future of plants and animals that exist only with the help of humans? Sure, we can manage everything a lot more easily and maybe even humans would be genetically engineer to be more manageable also.

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