That's a Wrap!

Category: Chatter
Posted by Katherine Sharpe at 2:58 PM

Hard to believe it's already been two weeks, but the Microcosm edition of the ScienceBlogs Book Club has come to an end. Please stay tuned in this spot for news about future installments of the Club. If you have any comments or suggestions about what you'd like to see in the future, or how we can make the Club better, please leave them in the comments below, or drop us an email. We'd love to hear from you.

Photo by seriykotik1970 on Flickr.

7 Comments

Dear Prudence

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Posted by Jessica Snyder Sachs at 12:16 PM

I think Carl gets right to the heart of the issue both in this online conversation and in his book. "Are we really just getting started thinking about this stuff?" he asks.

In some cases, it seems that regulators are forcing researchers to go to near-impossible lengths to ensure safety despite no conceivable risk. (Hillman's cavity-fighting tooth bug?) In other cases, researchers appear to be rushing ahead with no one stopping them.

Carl highlights what I consider a prime example of the latter issue in "Darwin at the Drugstore" (subsection "Skin of the Frog"). He describes how Michael Zasloff, the researcher who first began developing antimicrobial peptides (AMPs) as a new class of anti-infectives felt sure that bacteria could never develop resistance to them.

It took a clever evolutionary biologist, McGill's Graham Bell, just one summer to prove Zasloff wrong.

But that hasn't stopped other researchers from rushing forward with new AMP "antibiotics," some of which have now entered clinical trials.

Why does that make some, including myself, so nervous?

Antimicrobial peptides are the human immune system's front line of defense. As part of a concerted immune response, they don't prompt the evolution of resistance in bacteria. But when used in isolation (like an antibiotic), we now know they can and do breed resistance.

So are we risking the rise of genes that will make bacteria resistant to the body's own AMPs? We've seen how fast antibiotic-resistance genes proliferated through the bacterial world over the last 60 years. There's no turning back the clock on that one. But this ups the ante!

So back to Carl's wise question: "Are we really just getting started thinking about this stuff?"

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The Risk of Nature, The Nature of Risk

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Posted by Carl Zimmer at 10:26 AM

It is a little weird to think of engineered bacteria living in your mouth or your gut, fighting cavities or Crohn's disease. I'll admit I feel a twinge just thinking about it. But is that because I have some intuition of the risks of ingesting such creatures? I doubt it. I think it's just focusing my attention on the prospect of some living thing living inside me. But we're already packed with thousands of species, and we regularly get infected (or maybe I should just say colonized) with new microbes. We even purposefully take in bacteria for our well-being when we proudly spoon yogurt into our mouths.

Does that mean that there's absolutely no possible risk from swallowing bacteria loaded with human immune signal genes? No. We might guess that these genes would put these bacteria at a competitive disadvantage against the other bacteria struggling to survive in our guts. But that's a hypothesis. Judging the risks of these kinds of organisms is a lot harder than judging the risks of a cigarette or an asbestos factory. The microbes can evolve and they can pass their genes on to other microbes. Their effects may depend on the other species around them. This is true both for engineered microbes inside of us and for engineered crops and other free-living creatures in the wild. In both cases, we're introducing new players into ecosystems, and ecosystems are horrendously complex things. I've been looking over a new report from the National Academies of Sciences on the risks of genetically engineered organisms, and it deals mostly in experiments that still need to be done, not insights from past experiments. Are we really just getting started thinking about this stuff?

1 Comments

Horizontal Gene Transfer

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Posted by John Dennehy at 10:17 AM

Back in the 1970s, a scientist named Ananda Chakrabarty received the first patent for a genetically modified lifeform, an oil eating "Superbug" from the bacterial strain Pseudomonas putida. The feat was doubly hailed as a major step in bioremediation and a travesty of nature. In the long run, Chakrabarty's Superbug was a failure. It was unable to survive in the wild, unable to compete with native bacteria, and unable to move towards food sources.

The moral of the story is that it is very difficult to tinker with nature and produce an organism that can survive outside the rarefied confines of the laboratory. It takes a certain amount of hubris to believe that we can outdo 4 billion years of natural selection.

Genetic engineering? Nature does it all the time. Scientists call it horizontal gene transfer.

Bacteria can share antibiotic resistance genes. Viruses often encode virulence factors that make bacteria make you sick. Among eukaryotes, examples of horizontal gene transfer are popping up every day among organisms as diverse as plants, nematodes, beetles, and yeast. Even human--gasp--may be riddled with the remnants of horizontal gene transfers: transposons, "jumping genes", retroviruses, B chromosomes, even our organelles.

Engineering life is as old as life itself. We may be the first to do so in a conscious directed manner, but let's not kid ourselves into thinking we are the first. There is no doubt there will be mistakes made along the way, but fears of Frankenstein fauna overwhelming nature are vastly overstated. Genetic engineering has already overwhelmingly benefited our lives in ways that most of us are unaware of. Simply put, the benefits have outweighed the costs by several orders of magnitude.

Chakrabarty, A M; Mylroie, J R; Friello, D A & Vacca, J G (1975), "Transformation of Pseudomonas putida and Escherichia coli with plasmid-linked drug-resistance factor DNA.", Proc. Natl. Acad. Sci. U.S.A. 72 (9): 3647-51, 1975 Sep, PMID:1103151

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Where's the Line?

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Posted by Jessica Snyder Sachs at 10:52 AM

Yikes. Carl, how am I ever going to get that "parahuman" image out of my head!

I get your point. This image evokes the abhorrent reaction that early critics had against the idea of tinkering with any life, even "mere" E. coli.

Most people start to squirm when the transgenics concerns animals, especially when it produces visible "mutations." Today, I suppose that most people are comfortable with the idea of transgenic E. coli churning out useful chemicals inside sealed vats. We harvest and purify the chemicals. No harm done. Right?

So let's take the safety question one step further. In researching Good Germs, Bad Germs, I spent time with researchers who were busy seeding people's bodies with transgenic bacteria. Government regulators remain extremely jumpy about such research. For good reason?

One of the first examples involved using E. coli's kissing cousin, salmonella, to destroy cancer tumors. Researchers engineered the microbe to express a tumor destroying drug--but only when it reached cancerous tissue. It never went beyond one small clinical trial in one hospital, given the daunting task of convincing FDA regulators to approve expanded use.

Meanwhile, down in Florida, Jeffrey Hillman has spent a decade convincing the FDA to allow him to use his cavity-fighting Strep. mutans. Hillman isolated an unusually aggressive strain of this ubiquitous tooth bug and showed that it would elbow out a person's native Strep. mutans. He then engineered it to secrete alcohol (not enough to get you tipsy) instead of tooth-eroding acid.

Before allowing Hillman to introduce the bug into human mouths, FDA regulators required him to cripple it--so it could be removed in case of trouble. What kind of trouble? No one could say. But this is weird stuff, right?

Bottom line, Hillman knocked out the bug's ability to create a vital amino acid. So volunteers must feed it with a special mouth rinse to keep it alive.

A cavity-fighting tooth bug may not be a problem if it escaped and took up residents in other mouths. Heck, why not spread such a good thing?

But what about a microbe engineered with the ability to turn off the human immune system? That's what Lothar Steidler has created in Europe. In clinical trials, he's using it to treat patients with advanced cases of agonizing Crohn's disease--in which the immune system attacks the intestinal lining.

Here's the part that will scare some people: Steidler took a cheese bacterium and gave it a human gene for IL-10, the cytokine that tells the immune system to "stand down." He, too, knocked out genes to nutritionally cripple his transgenic. What's more, he did so in an elegant way that ensures that the bug can neither repair itself (to become nutritionally competent) nor spread its IL-10 gene to other bugs without making them nutritional cripples as well.

So does this stuff cross a line? Is it wildly reckless or the future of medicine?

3 Comments

Engineering Life: The Dog that Didn't Bark in the Night

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Posted by Carl Zimmer at 5:25 AM

Imagine that mad scientists defied nature and violated the barriers between species. They injected human DNA into non-human creatures, altering their genomes into chimeras--unnatural fusions of man and beast. The goal of the scientists was to enslave these creatures, to exploit their cellular machinery for human gain. The creatures began to produce human proteins, so many of them that they become sick, in some cases even dying. The scientists harvest the proteins, and then, breaching the sacred barrier between species yet again, people injected the unnatural molecules into their own bodies.

This may sound like a futuristic nightmare, the kind that we will only experience if we neglect our moral compass and let science go berserk. But it is actually happening right now. Today millions of people with diabetes will inject themselves with insulin that was produced by E. coli.

The fact that no one is disturbed by this state of affairs says a lot. It's like the curious incident of the dog in the night-time Sherlock Holmes notes in the story "Silver Blaze." When a Scotland Yard detective replies, "The dog did nothing in the night-time," Holmes replies, "that was the curious incident." But thirty years ago the dog was barking loudly.

In the early 1970s, a handful of scientists realized that they might be able to insert genes from other species into E. coli. They chose E. coli because, as I explain in my book Microcosm, it was the organism they knew best. With that knowledge came the power to manipulate it. Scientists figured out how to use some enzymes made by E. coli to snip segments of DNA out of the cells of animals. Then they loaded the segments onto tiny rings of DNA called plasmids, and injected the plasmids into E. coli. In 1973 Herbert Boyer, a biologist at the University of California, San Francisco, announced that he and his colleagues had endowed E. coli with DNA from an African clawed frog.

Boyer and others wondered if engineered E. coli might not just be able to carry alien DNA. Maybe it could read those new genes and make proteins from them. The bacteria could become biochemical factories.

A race began. Boyer and colleagues in California vied with a team of Harvard scientists headed by Walter Gilbert to be the first to engineer E. coli carrying the human insulin gene. At the time, diabetics could only get their insulin from the pancreases of pigs. E. coli might be able to create it in vast amounts from little more than sugar. By 1980 the race was won: Boyer's team had created an insulin-spewing E. coli. Their start-up company, Genentech, passed on the bugs to the pharmaceutical giant Eli Lilly, which breeding it in gigantic fermentation tanks.

In those few frenzied years of scientific research, the world shuddered at the thought of E. coli carrying alien genes. It could trigger unspeakable disasters, they thought. Insulin-producing E. coli might escape from their tanks, take up residence in people's guts, and cause epidemics of diabetic comas. They might spread cancer viruses, or some other unnatural plague. Erwin Chargaff, an eminent Columbia University biologist, called genetic engineering "an irreversible attack on the biosphere."

"The world is given to us on loan," he warned. "We come and we go; and after a time we leave earth and air and water to others who come after us. My generation, or perhaps the one preceding mine, has been the first to engage, under the leadership of the exact sciences,in a destructive colonial warfare against nature. The future will curse us for it."

At the same time, people warned that we were doing the unnatural, something that humans were not meant to do. "We can now transform that evolutionary tree into a network," declared Robert Sinsheimer, a biologist at the University of California, Santa Cruz. "We can merge genes of most diverse origin--from plant or insect, from fungus or man as we wish."

It was not a power that Sinsheimer thought we could handle. "We are becoming creators--makers of new forms of life--creations that we cannot undo, that will live on long after us, that will evolve according to their own destiny. What are the responsibilities of creators--for our creations and for all the living world into which we bring our inventions?"

Engineering E. coli came to be known as the Frankenstein project. The protests sometimes took on almost religious tones. Tampering with DNA, the MIT biologist Jonathan King declared, was "sacrilegious." Two political activists, Ted Howard and Jeremy Rifkin, condemned genetic engineering in a book called Who Should Play God?

It is striking to look back at this controversy from 2008. We suffered no epidemic of diabetic comas, no cancer viruses spread by E. coli from host to host. None of the dire warnings about engineered E. coli, in fact, came to pass. It appears that the safeguards put in place were good enough, and that engineered E. coli could not compete with its wild cousins. Scientists continued to engineer E. coli, and today it can make all manner of substances, from blood-thinners to jet fuel.

Despite all these bacteria suffering the indignity of being violated with human genes, no one seems to care. No one thinks the dignity of E. coli has been compromised. I have not heard of anyone refusing blood-thinners or insulin because it was produced from human genes put inside another species. In Europe, where protests over genetically modified plants and animals rage today, few seem to be bothered by the fact that a lot of cheese is produced with a cow's enzyme, chymosin, made by E. coli rather than cows. In fact, this cheese is labeled organic, because it's produced with "real" chymosin, rather than "artificial" chemicals.

I think that the story of engineered E. coli is an important one to bear in mind these days. Today we are faced with intense debates about whether it's right to create chimeras--a mouse that carries human neurons, for example. Headlines assault us with the danger that scientists will be playing God by creating life from scratch. We are revisiting old ground.

There's no question that scientists must think carefully about the potential risks of engineered organisms. And we must beware that we don't try to use genetic engineering to fix problems it can't fix. Diabetes can be controlled with insulin from E. coli, but it can't be cured with biotechnology. In fact, diabetes has exploded since Lilly started producing the stuff from bacteria.

But it's also important to bear in mind how easy it is to be terrified by a science-fiction caricature of what's really going on in synthetic biology labs. We have a profound distrust of what seems unnatural, such as crossing species boundaries. Yet a casual glance at E. coli's genome demonstrates that nature has been inserting foreign genes into it by the hundreds for millions of years. Our own genome is not immune from these violations. We carry the remains of thousands of viruses in our DNA, and most people on Earth may even carry genes inherited from another species of human--Neanderthals. We may be disgusted by the thought of violating species boundaries because of deeply ingrained instincts. But that disgust is an unreliable guide to the realities of biology, whether that biology is in E. coli or in ourselves.

[Picture: "The Young Family," by Patrician Piccini (2002-3). Wikipedia]

16 Comments

Chemistry vs. Biology

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Posted by Jessica Snyder Sachs at 4:14 PM

Carl, of course, is right in that it wasn't long ago that biologists scoffed at the idea of bacteria being more than bags of chemistry. Carl's thoughtful reply to my question included what, for me, is the best distillation of what virus's "are." He writes,

"So viruses may or may not be alive, but they are definitely a part of life."

And as John and several commenters point out, viruses sure as hell evolve!

Still, I find myself in the gotta-have-metabolism camp. To me, that's the dividing line between chemistry and biology.

As Carl notes in the section "The Shape of Life," (page 20), "But on their own, genes are dead, their instructions are meaningless."

I've heard viruses described as "escaped genes" ... albeit inside nifty protein packages. But as Carl says, MICROCOSM is less about distilling definitions as it is about understanding the rules. In that vein, on page 21, he writes,

"The most obvious thing one notices about E. coli is that one can notice E. coli at all. It is not a hazy cloud of molecules. It is a densely stuffed package with an inside and an outside."

So life has "boundaries," an inside and an outside that must be actively maintained.

As cool as bacteriophages look with their lunar lander profile, they are mere snarls of chemicals in and of themselves.

2 Comments

What Is Life? Skip the Definitions, Stick to the Rules

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Posted by Carl Zimmer at 9:48 PM

Jessica asked if I think viruses are alive. John has given his opinion. I will waffle, but I hope in an interesting way. The hard thing about answering that question is that we'd have to agree on what it means to be alive.

We all have a sense that we know what's alive and what's not, but I think that sense is really just an intuition. We use different circuits in our brains for recognizing biological motion, for example, as opposed to the motion of rocks or cars or other dead things. But the trouble comes when we try to turn that intuition into definition. We can see that things that look alive to us--tigers, roses, lobsters--share some things in common. And when we get tools to let us see new things, such as bacteria, we wonder, are they like us--in other words, are they alive? I find it interesting that in the nineteenth century, bacteria seemed to be at the hazy border of life and non-life. They seemed to be featureless bags of protoplasm. That was why the research on E. coli I write about in Microcosm was so astonishing. Down to many fine details, E. coli is a lot like us. Their genes are made of DNA. So are ours. They use a genetic code to read those genes and build corresponding proteins out of amino acids. So do we. There are actually dozens and dozens of different amino acids in nature, but E. coli only uses 20 of them to build proteins. We use a nearly identical set. Nobody would claim that E. coli is not alive anymore, because it is so much like us.

But just making a list of traits shared by us and E. coli is not a good definition of life. All known living things use the same set of amino acids. Or at least they did till some scientists engineered E. coli to use "unnatural" amino acids a few years ago. Are they no longer alive? Perhaps there are just a few basic things that qualify somehting as alive. A lot of people like to put metabolism on that short list--the ability to take in food and turn it into living matter. Some would say viruses are not alive, because they don't have their own metabolism. The classic picture of a virus is a package of genes that uses a host's cells to make more packages of genes. Yet some viruses appear to grow and undergo other changes outside their hosts, making this a dubious standard.

I also think it's a mistake to try to cordon off viruses in some non-living quarantine because they evolve, and their evolution is intertwined with the evolution of their hosts. A sizeable chunk of E. coli's genome is made up of genes delivered by viruses--many of which are essential to the microbe's survival. The same goes for all the microbes in the ocean, the soil, and in our bodies. I think now of life as a global matrix of genes, shuttling from node to node and changing over time.

So viruses may or may not be alive, but they are definitely a part of life.

I think it's better to think about life not in terms of hard definitions, but in terms of rules--ways in which species tend to work, no matter how different they seem superficially. The fact that all living things use 20 amino acids is not part of the definition of life, but it certainly is a rule that applies to all life on Earth outside of laboratories. Some scientists think this rule probably the result of some sort of frozen accident early in the evolution of life, or perhaps natural selection zeroing in on the most efficient or reliable system for building proteins.

In the book I also point out other surprisingly widespread rules of life. Life, for example, is robust. In other words, the ways in which genes interact allows living things to stay stable in a world full of change. E. coli copes with rising and falling temperatures, times of feast and famine--all sorts of change--while maintaining an even keel. Its robustness, like our own, is the result of how its genes are organized, like the parts of an airplane. (That's why engineers are now helping make sense of E. coli's genes, using the same tools they might use to build autopilot systems.) But that doesn't necessarily mean that life started out robust to begin with. In each lineage, robustness was a good long-term strategy.

When I imagine the day when we discover alien life, I wonder about whether aliens will be robust too. I also wonder if they will also obey the rules of Earthly life. E. coli and other microbes are surprisingly social, for example, communicating, cooperating, and sometimes even killing themselves for their fellow microbe. Perhaps to be alive is to be social? And the fact that E. coli ages like we do--as an evolutionary strategy to cope with the inescapable decay of biological molecules--makes me wonder if aliens get old too.

10 Comments

What is Life?

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Posted by John Dennehy at 11:24 AM

It has been suggested that the first posts of this book club be devoted to the Universal Rules of Life. So... What is life?

Jessica asks,

Carl, twice in the book you refer to viruses as "creatures." Perhaps you used the word metaphorically. In any case I'd love to know whether you think viruses qualify as being alive, and I'd love to hear your reasoning either way.

Historically, viruses have been considered non-living. Some of the first discoverers of viruses, Frederick Twort for example, thought they were enzymes secreted by bacteria. Other biologists, such as Felix d'Herelle, contended that viruses were alive. The distinction lies largely on how "life" is defined.

Viruses certainly do straddle the borderline between the living and the non-living. In some ways, they resemble chemicals. In essence, they are nucleic acids encased in protein. They are inert much of the time, only becoming active on finding and entering a host. They are unable to reproduce on their own. They cannot consume food, breathe, chase prey, respond to the environment in ways typical of the organisms most familiar to us.

But many organisms we classify as living occasionally show the inability to conduct activities we associate with life. For example, is reproducing on its own truly a characteristic of life? Obligate symbioses are common in the biological world. These organisms are unable to survive without the assistance of another organism. For example, some flowers cannot reproduce without assistance from bees. I would argue we are all obligate symbiotes deep down.

The best definition of life I have encountered comes from Salvatore Luria, he of the Slot Machine Experiment ably described by Zimmer in Microcosm.

"An organism is the unit element of a continuous lineage with an individual evolutionary history."

SE Luria, JE Darnell, D Baltimore and A Campbell (1978). General Virology, 3rd Edn. John Wiley & Sons, New York, p4 of 578.

With this definition, viruses are unequivocally alive. I've blogged briefly about this definition previously here.

Photo: A thin section of T4 phages hitting a microcolony of E. coli K-12 by John Wertz.

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