Growing Pressure to Stop Antibiotics In Agriculture

This Drug Discovery & Development 4 Jan 2010 article summarizes some of the current agitation for US policy changes:

(…) Researchers say the overuse of antibiotics in humans and animals has led to a plague of drug-resistant infections that killed more than 65,000 people in the U.S. last year – more than prostate and breast cancer combined. And in a nation that used about 35 million pounds of antibiotics last year, 70 percent of the drugs went to pigs, chickens and cows. Worldwide, it’s 50 percent.

“This is a living breathing problem, it’s the big bad wolf and it’s knocking at our door,” said Dr. Vance Fowler, an infectious disease specialist at Duke University. “It’s here. It’s arrived.”

The rise in the use of antibiotics is part of a growing problem of soaring drug resistance worldwide, The Associated Press found in a six-month look at the issue. As a result, killer diseases like malaria, tuberculosis and staph are resurging in new and more deadly forms.

In response, the pressure against the use of antibiotics in agriculture is rising. The World Health Organization concluded this year that surging antibiotic resistance is one of the leading threats to human health, and the White House last month said the problem is “urgent.”

“If we’re not careful with antibiotics and the programs to administer them, we’re going to be in a post antibiotic era,” said Dr. Thomas Frieden, who was tapped to lead the Centers for Disease Control and Prevention this year.

(…) Here’s how it happens: In the early ’90s, farmers in several countries, including the U.S., started feeding animals fluoroquinolones, a family of antibiotics that includes drugs such as ciprofloxacin. In the following years, the once powerful antibiotic Cipro stopped working 80 percent of the time on some of the deadliest human infections it used to wipe out. Twelve years later, the New England Journal of Medicine published a study linking people infected with a Cipro-resistant bacteria to pork they had eaten.

(…) Johns Hopkins University health sciences professor Ellen Silbergeld, who has reviewed every major study on this issue, said there’s no doubt drug use in farm animals is a “major driver of antimicrobial resistance worldwide.”

The article includes an anecdote regarding a Missouri pig farmer who acquired a resistant strep infection from a boar tusking. His experience prompted him to eliminate antibiotics from his farm. His success echos reports from Dr. Greg Cook [University of Otago]  that Danish and Dutch studies showed industrial antibiotics did not in fact benefit the farmers:

(…) Back in Missouri, farmer Kremer finally found an antibiotic that worked on his leg. After being released from the hospital, Kremer tested his pigs. The results showed they were resistant to all the same drugs he was.

Kremer tossed his hypodermic needles, sacked his buckets of antibiotic-laced feed, slaughtered his herd and started anew.

“I was wearing a syringe, like a holster, like a gun, because my pigs were all sick,” he recalled. “I was really getting so sick and aggravated at what I was doing. I said, ‘This isn’t working.'”

Today, when Kremer steps out of his dusty and dented pickup truck and walks toward the open-air barn in the foothills of the Ozark Mountains, the animals come running. They snort and root at his knee-high gum boots. There are no gates corralling the 180 pigs in this barn. He points to a mound of composting manure.

“There’s no antibiotics in there,” he says proudly.

Kremer sells about 1,200 pigs annually. And a year after “kicking the habit,” he says he saved about $16,000 in vet bills, vaccinations and antibiotics.

“I don’t know why it took me that long to wake up to the fact that what we were doing, it was not the right thing to do and that there were alternatives,” says Kremer, stooping to scratch a pig behind the ear. “We were just basically killing ourselves and society by doing this.”

PAR – Predicting antibiotic resistance

In my previous post I referred readers to Jim Caryl’s The Gene Gym blog at Jim’s current research is funded by the European Commission project PAR – Predicting antibiotic resistance. Summary:

Antibiotic resistance represents a rapidly growing global health problem caused by the use and misuse of antibiotics and spread of resistant bacteria as well as the lack of industrial development of new antibiotics. The urgency of the resistance problem makes the development of experimental and theoretical tools and methods to understand and predict (and by inference prevent) the development of antibiotic resistance a high priority. This project aims to describe and predict the dynamics of antibiotic resistance development at the level of the drug target, the microbe and the host.. The obtained results will have general biological implications with regard to molecular evolution and bacterial adaptation, virulence and transmission. Most importantly, our results will generate strategies to reduce the rate of resistance of development.

A good place to begin your Gene Gym reading is this article on Bacterial Fitness. Jim’s earlier blog is also a good source of science on antibiotic resistance.

Craig Venter unveils "synthetic life"

“We can now begin working on our ultimate objective of synthesizing a minimal cell containing only the genes necessary to sustain life in its simplest form. This will help us better understand how cells work.” – Dan Gibson

We’ve been following the efforts of the Venter Institute to develop a synthetic bacterial cell. The goal of this research has been to achieve the capability to “understand by building” as applied to the cell.

Last night we noted that was hosting a Craig Venter press conference where on May 20th he announced their success. The talk is a bit dry compared to the typical TED Talk, but we think you will find it exciting. Venter describes several of the unexpected roadblocks encountered in the project, commenting to the effect that “over 99% of our experiments were failures”.

You can read a summary in a Venter/Gibson WSJ op-ed which begins:

In 1995, we reported the DNA sequences for the first two cellular genomes. Nowadays genome sequences, which contain the genetic instructions for an organism, are routinely obtained and deposited in computer databases.

Last week, we reported that this process can be reversed. The digitized DNA information of Mycoplasma mycoides, a simple bacterium, can now be brought to life.

To make this happen, our group of 25 researchers had to decipher this bacterium’s set of instructions, synthesize them, and then express them in a recipient cell. Many technical hurdles had to be overcome. But 15 years and $40 million worth of research later, we are able to combine all of these steps and produce synthetic cells in the laboratory.

So what is new and unique about what we did? The process of synthesizing a cell began at a computer. We started with the more than one million letters of genetic instructions for Mycoplasma mycoides, and then made slight modifications to its DNA sequence. First, we deleted 4,000 letters, which removed the function of two genes. We then replaced 10 genes with four “watermark” sequences. These watermark sequences are each over 1,000 letters in length and can be decoded to reveal the names of people, famous quotations and a website address. The entire sequence of DNA letters was then partitioned into 1,100 pieces, and each was synthesized using four different bottles of chemicals that make up DNA. These DNA fragments were designed such that adjacent pieces contained an 80-letter overlap, which facilitated the assembly process by providing unique regions where the synthetic pieces could join.

For the in-depth results you can access at Science Express: Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome [full text available here as PDF]. And the Venter Institute press release.

What does this accomplishment mean? First, the pace of synthetic biology has been much slower than we hoped (and slower than advocates like Stanford’s Drew Endy forecast). Second, the technical feat of assembling a 1 million letter DNA sequence is still staggering. E.g., just consider the error-detection/correction challenge — this is the debugging method developed to isolate a synthesis error in the final stages:

The initial synthesis of the synthetic genome did not result in any viable cells so the JCVI team developed an error correction method to test that each cassette they constructed was biologically functional. They did this by using a combination of 100 kb natural and synthetic segments of DNA to produce semi-synthetic genomes. This approach allowed for the testing of each synthetic segment in combination with 10 natural segments for their capacity to be transplanted and form new cells. Ten out of 11 synthetic fragments resulted in viable cells; therefore the team narrowed the issue down to a single 100 kb cassette. DNA sequencing revealed that a single base pair deletion in an essential gene was responsible for the unsuccessful transplants. Once this one base pair error was corrected, the first viable synthetic cell was produced.

I feel confident in predicting that Venter will not be building a pilot plant for his synthetic biofuel next year. But I would definitely not bet against important breakthroughs in the next five or so years. At least I hope the promise is not always “just five years ahead”. Here’s Venter/Gibson from the WSJ op-ed on one of our priority wishes, that of rapid-response vaccine development:

(…) We are currently working on the design of new cells that can much more efficiently capture carbon dioxide and “fix” (or incorporate) the carbon into new fuel molecules, new food oils, and new biologically derived sources of plastic and chemicals. We already have funding from the National Institutes of Health to use our synthetic DNA tools to build synthetic segments of every known flu virus so that we can rapidly build new vaccine candidates in less than 24 hours. We are also being funded to see if we can take sets of genes out of bacteria to design new synthetic pathways to make antibiotic compounds that are currently too complex for chemists to make.

One (of many) things we don’t yet grasp is “why did Venter switch from the original goal of synthesizing the minimal organism?” Please comment if you know. Meanwhile, we have this from the useful FAQ:

Q: What are the next steps for this research at JCVI?

A: The work to create the first self-replicating, synthetic bacterial cell was an important proof of concept. The team at JCVI has learned a lot from the nearly 15 years it has taken to get to this successful stage. From this proof of concept experiment the team is now ready to build more complex organisms with useful properties. For example, many, including scientists at SGI, are already using available sequencing information to engineer cells that can produce energy, pharmaceuticals, and industrial compounds, and sequester carbon dioxide. The team at JCVI is already working on their ultimate objective, which has been to synthesize a minimal cell that has only the machinery necessary for independent life. Now that a cell can be synthesized from a synthetic genome in a simple near-minimal bacterial cell, it becomes possible for the team to test for the functionality of a genome. They can whittle away non-essential DNA regions from the synthetic genome and repeat transplantation experiments until no more genes can be disrupted and the genome is as small as possible. This minimal bacteria cell will enable a greater understanding of the function of every gene in a cell and a new vision of cells as understandable machines comprised of biological parts of known function.

Greg du Toit: African wildlife you've never seen before

Wildlife photographer Greg du Toit’s hardships paid off in these amazing images.

(…) he sat submerged in their watering hole for three months. The defiant photographer had endured a year of failed attempts at getting the right picture after building hides and digging trenches near the animals’ drinking spot. In a final desperate effort, the 32-year-old decided to take the plunge and climb into the murky pool with his camera and ended up contracting several tropical diseases.

Please continue reading…

True innovation is rare in evolutionary biology

Don Monroe provokes learning with each new post. An excerpt on what we have learned about the post-Cambrian:

(…) In The Plausibility of Life, Marc Kirschner and John Gerhart highlight another critical facet of this amazing period: since that period of innovation, no more than one new animal type has appeared. The diversity we enjoy today is built from basic parts that were “invented” in the Cambrian explosion.

Rather than get into how and why this happened, for now let’s just regard it as an observational fact from the fossil record:

True innovation is rare.

(…) For whatever reason, the evolutionary history of life is a series of one-time innovations. After they are adopted, these “core processes” change very little, even though they have eons of time to do so. That doesn’t mean that the organisms themselves stay the same–far from it. But they use the core processes in different ways, just as a bat wing is built in the same way as the human hand.

Please continue reading…

An Interview With E.O. Wilson, the Father of the Encyclopedia of Life

David Pogue offers a “much longer version of my interview with E.O. Wilson (friends call him Ed), the two-time Pulitzer Prize winner, naturalist and Harvard research professor who’s the father of the Encyclopedia of Life.” An excerpt:

DP: And what do you say to people who think, “Oh. Oh, how interesting. A database for scientists.” I mean, is there a greater purpose to a Web site like this?

EOW: The public will have this unlimited encyclopedia, where it can browse [at]. Where individual students can do their own research projects. Where you can make your own field guide wherever you’re going. It will tell you what the butterflies are of Oregon, or maybe you’re hoping to make a trip to Costa Rica and the whole family would like to see turtles. In time, you’ll be able to do this with a few keystrokes.

DP: So I understand that the Encyclopedia will operate Wikipedia-style, with contributions from the public, which are then approved by experts?

EOW: The world is full of amateurs: gifted amateurs, devoted amateurs. You can pick almost any group that has any kind of intrinsic interest in it, from dragonflies to pill bugs to orb-weaving spiders. Anybody can pick up information in interesting places, find new species or rediscover what was thought to be a vanished species, or some new biological fact about a species already known, and can provide that right into The Encyclopedia of Life.

Norman Borlaug: green revolutionary

…when journalist Gregg Easterbrook sought a publisher for a popular biography, “they said he was boring,” the self-described “environmental optimist” says. “If he’d killed someone instead of saving hundreds of millions of lives, then they’d have been interested.”

Borlaug is almost unknown, at least in big media, though he contributed more than any other researcher to the “green revolution”. Borlaug’s recent biography The Man Who Fed the World is a must-read.

Paradoxically, 1968 also saw the genesis of an environmentalist dogma that was pessimistic about humanity’s capacity to feed itself. In that year–when the global population growth rate peaked, at 2 percent per year–Paul Ehrlich published The Population Bomb, intoning, “The battle to feed all of humanity is over. … Hundreds of millions of people will starve to death in spite of any crash programs.” The madding crowd of “stinking hot” Delhi was odious to Ehrlich: “My wife and daughter and I … entered a crowded slum area. … People, people, people, people. … [We] were, frankly, frightened.” It was a “fantasy,” he said, that India would ever feed itself. Yet Borlaug’s program delivered such stunning results that India issued a 1968 stamp commemorating the “wheat revolution,” and by 1974 it was self-sufficient in all cereals.

Nonetheless, a neo-Malthusian fear of overpopulation became endemic to environmentalist thinking. Science philosopher and Arts and Letters Daily founder Denis Dutton says, “Well-fed Greens flaunt their concern for the planet but are indifferent, even hostile, to the world’s poor with whom they share it. Some Greens I knew acted for all the world as though they relished the idea of a coming worldwide famine, much as fundamentalists ghoulishly looked forward to Armageddon.” Dutton, who served in the Peace Corps, personally saw the Green Revolution benefit India. “For the catastrophist, India becoming a food exporter was disturbing,” he says. “This wasn’t supposed to happen. They blame Borlaug for spoiling the fun.”

Not all Borlaug’s critics were catastrophists: some opposed the intensity of his agriculture, especially its use of inorganic fertilizer. Borlaug acknowledges the need for care, but he says the “natural” alternative, cow manure, “would require us to increase the world’s cattle population from around 1.5 billion to some 10 billion.” As he dryly observed in a 2003 TV interview, “Producing food for 6.2 billion people … is not simple.” He added, “[Organic approaches] can only feed four billion–I don’t see two billion volunteers to disappear.”

Raised on a farm, Borlaug thinks many of his detractors would benefit from a week or two in the fields. He cites Ghanaian farmers who use no-till agriculture (that is, plant waste is left to improve the humus and reduce erosion) and control weeds with herbicides. Their lives are improved by the reduction in weeding. “Less backache, you see,” he once said. “You know, it’s amazing how often campaigners in rich countries think poor people don’t get backache.”

Why didn’t Africa benefit from Borlaug’s advanced wheat? In short, no irrigation, soils, politics, roads.

Many thought the work that earned Borlaug his Nobel brought an end to stem rust, but it is back, in the form of a variant called Ug99, which emerged in Uganda and spread to Kenya and Ethiopia. “If it continues unchecked,” says Borlaug, “the consequences will be ruinous.”

…The reasons for failure in Africa are complex. “Irrigation is first,” explains Michael Lipton of the University of Sussex’s Poverty Research Unit. “In sub-Saharan Africa, 4 percent of cropland is irrigated. In South and East Asia it’s nearer 40 percent.”

Then there’s soil. “Africa’s soils … [are] equivalent–and were once adjacent–to the Cerrado’s acid soils,” Borlaug says. The Cerrado, an area that extends across central Brazil, historically had some of the least productive soil in the world. But improved crop varieties of the sort that Borlaug created–along with liming, fertilizer, and low- or no-till methods–have led to the single largest increase in arable-land usage in the last 50 years.

Politics, both regional and global, were and are another hindrance. “If the Green Revolution in India was proposed to the World Bank today, it would be turned down,” says Rob Paarlberg, an agricultural-policy expert at Wellesley College. By the 1980s, he says, “public investment in roads, research, irrigation, fertilizers, and seeds was politically unacceptable to the Washington consensus on the right–and on the left, among environmentalists opposed to chemical fertilizers, road building, and irrigation projects.” Thus, real per capita levels of official development assistance for the agricultural sector in the poorest countries fell by nearly 50 percent between 1982 and 1995.

Finally, Borlaug says, “Africa needs roads. Roads bring know-how and fertilizer to farmers and ideas and business for commerce.” Africa, Borlaug argues, also needs concerted international help. Meanwhile, Ug99 has reached Yemen: from there, Borlaug warns, “it can reach Iraq, Iran, India, and Pakistan”–even the breadbaskets of Europe and America. A scramble is on to find resistant varieties, ensure that their yields will encourage farmers to adopt them, and produce sufficient tonnages of seed.

Last year, ABC, CBS, and NBC cameras were absent when Borlaug was presented with the Congressional Gold Medal…


Craig Venter publishes his diploid genome

Edge 221 is a fun issue, beginning with the translation from German of a Jordan Mejias’ report on the meeting at Brockman’s farm:

Was Evolution only an interlude? At the invitation of John Brockman, science luminaries such as J. Craig Venter, Freeman Dyson, Seth Lloyd, Robert Shapiro and others discussed the question: What is Life?

EASTOVER FARM, August 30th

It sounds like seaman’s yarn what the scientist with the look of a sea dog has in store for us. The suntanned adventurer with the close-clipped grey beard vaunts the ocean as a sea of bacteria and viruses, unimaginable in their varieties. And in their lifestyle, as we might call it. But what do organisms live off? Like man, not off air or love alone. There can be no life without nutrients, it is said. Not true, says the sea dog. Sometimes a source of energy is enough, for instance, when energy is abundantly provided by sunlight. Could that teach us anything about our very special form of life?

J. Craig Venter, the ingenious decoder of the genome, who takes time off to sail around the world on expeditions, balances his flip-flops on his naked feet as he tells us about such astounding phenomena of life. Us, that means a few hand-picked journalists and half a dozen stars of science, invited by John Brockman, the Guru of the all encompassing “Third Culture”, to his farm in Connecticut.

Relaxed, always open for a witty remark, but nevertheless with the indispensable seriousness, the scientific luminaries go to work under Brockman’s direction. He, the master of the easy, direct question that unfailingly draws out the most complicated answers, the hottest speculations and debates, has for today transferred his virtual salon, always accessible on the Internet under the name Edge, to a very real and idyllic summer’s day. This time the subject matter is nothing other than life itself. <more>

Edge offers links to several media reports on the new Venter Institute paper in Plos Biology. Here’s a brief report from ScienceNow:

For the first time, researchers have published the DNA sequence from both sets of chromosomes in a single person. That person is none other than pioneering genome researcher J. Craig Venter. The new sequence suggests that there is substantially more variation between humans than previously recognized and pushes personalized medicine a step closer.

In 2001, Celera Genomics, a company then headed by Venter, and, separately, the International Human Genome Project consortium each published a genetic blueprint for a human. To save time and money, both teams combined samples from several individuals and created composite genomes that contained only half of a human’s DNA. Humans have a diploid genome with 23 pairs of chromosomes–with one of each pair contributed by the father and the other by the mother—and the researchers hoped that these partial “haploid” genomes wouldn’t sacrifice much detail. Wrong, says a massive 31-page paper published in the October 2007 PLoS Biology by Venter, his colleagues at the J. Craig Venter Institute in Rockville, Maryland, and collaborators from three universities.

According to the study, haploid genomes underestimate the amount of genetic variation between individuals by a factor of 5. “We all had very naïve assumptions because we didn’t have that much data to go on,” says Venter.

Venter and co-workers compared his two haploid genomes to assess the differences between the DNA he inherited from his mother and that from his father. They looked for everything from easy-to-find differences in single bases to much more obscure variations in chunks of DNA sequence that had been inserted or deleted from chromosomes. All told, the analysis found more than 4 million variants between Venter’s maternal and paternal chromosomes. This suggests that humans differ by 0.5%, not 0.1% as suggested by earlier estimates. (Some researchers, however, note that recent studies of insertions and deletions have emphasized the same point.)

“This is a great study,” says Harvard University geneticist George Church, an early proponent of the Human Genome Project. “We need to have diploid genomes to sort out our full inheritance. If I walk in to a doctor, it isn’t going to do either of us any good if he just gets my dad’s genome.”

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End of "the Darwinian interlude"?

John Brockman just published the email exchange between Freeman Dyson and Richard Dawkins regarding Dyson’s essay “Our Biotech Future”. This is in Edge 221 with no direct link — just scroll down to The Reality Club.

As part of this year’s Edge Event at Eastover Farm in Bethlehem, CT, I invited three of the participants—Freeman Dyson, George Church, and Craig Venter—to come up a day early, which gave me an opportunity to talk to Dyson about his abovementioned essay in New York Review of Books entitled “Our Biotech Future”.

I also sent the link to the essay to Richard Dawkins, and asked if he would would comment on what Dyson termed the end of “the Darwinian interlude”.

Early the next morning, prior to the all-day discussion (which also included as participants Robert Shapiro, Dimitar Sasselov, and Seth Lloyd) Dawkins emailed his thoughts which I read to the group during the discussion following Dyson’s talk. [NOTE: Dawkins asked me to make it clear that his email below "was written hastily as a letter to you, and was not designed for publication, or indeed to be read out at a meeting of biologists at your farm!"].

Now Dyson has responded and the exchange is below.

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Craig Venter: The Bill Gates of Artificial Life?

There he goes again, says a group of scientists and activists alarmed by the latest rebel moves of J. Craig Venter.

I think that Duncan and ETC may be getting a bit more breathless than the facts merit. As best I can tell Venter is investing his own money towards the laudable goal of harnessing synthetic biology. See the end of Duncan’s post for some perspective.

Since butting heads with the scientific establishment during the sequencing of the human genome–and coming out rich and famous in the process–Venter has had the moxie and smarts to know just when it’s time to blend science with commerce.

This time he’s trying to cash in with a patent for artificial life–specifically, a designer microbe that Venter and his pals at the Venter Institute have been trying to assemble from scratch. In 1999, Venter and Nobel laureate Hamilton Smith used a simple bacterium called Mycoplasma genitalium to roughly figure out the minimal number of genes it would take for an organism to live. Since then they have been trying to synthesize this “minimal genome” inside a cell that could be augmented by additional genes to do things like produce hydrogen or gobble up carbon dioxide.

Three years ago, when I last visited Venter’s institute, located in Rockville, Maryland, he told me he and his colleagues were making great progress on finishing this artificial bug. But so far there has been no announcement of success. “This is not easy to do, to build a living organism from scratch,” he said at the time.

Whatever success or failure the team has had, Venter the businessman quietly filed an application last October that seeks to own the critter his lab wants to create. The U.S. Patent Office published the application (#20070122826) on May 31.

June 18, 2007: Addendum to Readers

After publishing this blog, a spokesperson for the Venter Institute e-mailed me to say that Craig Venter speaks often about the societal implications of synthetic biology. In 1998, the Institute of Genomic Research, founded by Venter, issued an ethical report on the topic authored by a team led by bioethicist Arthur Caplan of the University of Pennsylvania. In 2005, the policy group at the Venter Institute, along with MIT and the Center for Strategic and International Studies, were given a grant from the Sloan Foundation to review societal issues and laboratory practices surrounding synthetic genomics. (Check out the press release issued in 2005.) Their final report from this review will be issued in July. The Venter Institute spokesperson said that the ETC was invited to attend meetings and present comments, but apparently it did neither.

Venter seems determined to forge ahead with his work and with his patent–which is his prerogative as a scientist. It is also the prerogative of critics to continue to challenge Venter and others as they push science to the edge of what society may or may not tolerate at the moment. In between is the great mass of society that will undoubtedly pay scant attention to either side, although the outcome of this discussion may have far-reaching implications–if Venter is able to create a truly synthetic organism.

I plan to closely follow this issue and read the Sloan-funded report next month. Let’s pick up this discussion again then.

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