Biology's Coefficient

 

JOEL E. COHEN. Laboratory of PopulationsRockefeller University & Columbia University

Joel Cohen uses the tools of mathematics to deconstruct questions of life.

New York, New York© THE ROCKEFELLAR UNIVERSITY

In 1992, Joel Cohen received a phone call from a journalist at Discover magazine. The journalist asked Cohen, a professor of populations at Rockefeller University with doctorates in applied mathematics and public health, “How many people can the Earth hold?” Cohen replied honestly: “I said to him, ‘I don’t know. I’ll try to find out for you.’ I said to myself, ‘This is your business. You’re supposed to know! What’s the matter with you?’”

Cohen spent the next six weeks reading studies that estimated Earth’s human carrying capacity based on a variety of data, from water and land use to food production to mineral availability to energy. “The more I dug, the more fascinated I became that everybody had an answer, but none of the answers agreed,” says Cohen. “They were all based on different assumptions. . . . The substance just was not there.”

Cohen became so irritated with the answers available that he spent the next four and a half years compiling more than 60 studies and developing mathematical models of the planet’s human carrying capacity. The book and Science paper he ultimately published on the topic concluded that Earth’s human carrying capacity is dynamic, uncertain, and shaped by the interactions of populations, economics, the environment, and cultures. The ecological notion of carrying capacity, while excellent for describing antelope populations on the plains, is not a useful tool for thinking about the challenges facing humans.

“Mathematical thought is the railroad over which we carry the freight of scientific discoveries. And I’ve wanted to help lay a few additional tracks.”

This Protein Could Change Biotech Forever

ORIGINAL: Forbes

By Matthew Herper Forbes Staff

3/19/2013

It started with a quest to make better yogurt.
(Photo credit: Wikipedia)

A tiny molecular machine used by bacteria to kill attacking viruses could change the way that scientists edit the DNA of plants, animals and fungi, revolutionizing genetic engineering. The protein, called Cas9, is quite simply a way to more accurately cut a piece of DNA.

“This could significantly accelerate the rate of discovery in all areas of biology, including gene therapy in medicine, the generation of improved agricultural goods, and the engineering of energy-producing microbes,” says Luciano Marraffini of Rockefeller University.

The biotech revolution that created drugs like EPO for anemia and interferon for multiple sclerosis and crops like Monsanto‘s Roundup Ready soybeans was based on relatively crude methods for inserting a gene from one organism into another. For a decade some biologists have been touting a new approach, dubbed synthetic biology, that makes more genetic alterations in order to treat living things more like machines that can be engineered. The ability to make modular changes in the DNA of bacteria and primitive algae has resulted in drug and biofuel companies such as Amyris and LS9. But figuring out how to make changes in the genomes of more complicated organisms has been tough.

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Although it’s possible to insert a single gene from one species into another, it’s much harder to cut the genetic code in specific places to make real copy-editing possible. Two techniques for doing so were placed among the top innovations of 2012 by Science, and NIH director Francis Collins wrote in a blog post that they are “revealing tantalizing new possibilities for treating human diseases” in a blog post. But one, zinc finger nucleases, can cost $6,000 per edit, and a second, Transcription Activator-Like Effector Nucleases (TALENs), appears only a fifth as efficient as Cas9.

“It is spreading like wildfire from everyone who knows about it and it certainly is very tantalizing,” says George Church of Harvard University. “It’s easy to get in and start doing lots of experiments.”

Originally, Phillipe Horvath and Rodolphe Barrangou, scientists at Danesco, now part of DuPont, were hoping to find a better way to make yogurt. The bacteria used to culture milk are particularly prone to becoming infected with viruses that kill them, lowering productivity. For decades, researchers had realized that bacteria had strange, repeating patterns of DNA sequence scattered throughout their DNA, known as clustered regularly interspaced short palindromic repeats (CRISPR). Horvath and Barrangou figured out what these were: mug shots.

The bacteria were keeping track of tell-tale bits of genetic code from viruses that might try to infect them, and, somehow, they were using these codes to kill those viruses when they attacked. CRISPR was a primitive immune system. Horvath recognized that this knowledge could be used to create bacteria that were more resistant to infection, which would be useful in making yogurt and perhaps in manufacturing drugs. But he was quick to realize something else: somehow the bacteria had the ability to target specific bits of genetic code. If scientists could harness that, they would have a new way to edit DNA.

Horvath and Barrangou’s paper set off a race to figure out what the bacteria’s mysterious secret weapon was. Obviously, there was some kind of DNA-cutting enzyme, a protein that had the ability to cut genetic material.

Emmanuelle Charpentier of Umea University of Sweden had picked up hints of one likely protein. At a scientific conference, she struck up a friendship with Jennifer Doudna, a Howard Hughes Medical Institute investigator at UC Berkeley. Their transatlantic collaboration bloomed in part because Martin Jinek, a scientist in Doudna’s lab, spoke the same dialect of Polish as Krzysztof Chylinsk, one of Charpentier’s scientists. They named the protein they found CRISPR-associated system 9 — Cas9.

The Cas9 team: Emmanuelle Charpentier, Jennifer Doudna, Martin Jinek, Krzysztof Chylinski and Ines Fonfara.

In a paper published in Science last summer, they found that the bacteria combined Cas9 with genetic material to create “homing molecules” that attack viruses. Bacteria, like human beings and almost every other living thing, keeps its genetic code in a library of DNA molecules. But to use that code, the organism copies the DNA into a related molecule called RNA. Cas9 can be paired with an RNA transcript to target a matching DNA sequence and cut it. That kills viruses, but scientists use it to cut DNA in exactly the place they want. The result is not so much like using a word processor as a biology lab version of what movie editors had to do back when they spliced together pieces of film.

Church and his colleagues showed that they could use the system to make multiple edits at once to a cell’s DNA, and, better yet, industrialize their use. Feng Zheng, a former student of Church’s, also got it to work, and hopes to use it to better understand the brain. Both results were published in Science in January. Doudna’s own paper has been accepted by the electronic journal eLife. Doudna has started a company, Caribou Biosciences, to commercialize her work.

In the short term, Church says, the potential of Cas9 is that it could be used to study genetics in a way that was heretofore impossible. Let’s say there are three changes in the DNA in or around a gene that might cause a disease. Right now, it’s hard to study them directly. But now, Church says, you could take a cell from a person who has already had their DNA sequenced, as he is doing with his Personal Genome Project. Then you’d create what’s known as an induced pluripotent stem cell, a cell that behaves much like one in an embryo. After that, you could use Cas9 to change each of those DNA spelling changes.

The ability to do all of this in parallel is “what’s really going to blow things up,” says Northwestern University‘s Erik Sontheimer. Researchers could compare cells that are genetically identical except for single, specific changes. That could be hugely useful in, for instance, developing new drugs.

Recently, there was a bit of an internet uproar when some outlets took an interview Church gave a German newspaper out of context and made made it sound as if he were looking to clone Neanderthals. He’s not. But this is the kind of technology that one would use to bring back Neanderthals or, for that matter, mammoths, when their actual DNA is lost to time. Church has said that, in theory, this could be done by changing the genes of a human stem cell (in the case of a Neanderthal) or an elephant (in the case of the mammoth) to match a prehistoric relative. If you want to bring back ice age animals, Cas9 might be the way to do it.

Anything like that is a long way off. Right now, scientists are using this technology largely on cells in laboratory dishes, not on whole organisms. And the road from lab experiment to treatment is a long one. Sangamo Biosciences has been working to commercialize the earlier zinc finger nuclease technology as a form of medicine for more than a decade. Moving Cas9 out of the lab could take just as long. But that doesn’t make it any less tantalizing.

Genes Culled from Desert Soils Suggest Potential Medical Resource

ORIGINAL: Science Daily

ScienceDaily (May 27, 2012) — Despite their ecologic similarity, soils from three geographically distinct areas of the American southwest harbor vastly different collections of small, biosynthetic genes, a finding that suggests the existence of a far greater diversity of potentially useful products than was previously supposed. The research is published in the May issue of Applied and Environmental Microbiology.

Natural compounds have been the sources of the majority of new drugs approved by the US Food and Drug Administration, and bacteria have been the biggest single source of these therapeutically relevant compounds. Most bacterially-derived antibiotic and anticancer agents were discovered by culturing bacteria from environmental samples, and then examining the metabolites they produce in laboratory fermentation studies. But the vast majority of bacterial species cannot be cultured, which suggested that the world might be awash in potentially useful, but unknown bacterial metabolites.

In this study, Sean Brady of the Howard Hughes Medical Institute, Rockefeller University, New York, NY, and colleagues extracted DNA from soils from the Sonoran Desert of Arizona, the Anza Borrego section of the Sonoran Desert of California, and the Great Basin Desert of Utah. They used this DNA to construct very large metagenomic DNA libraries, and screened these libraries for three of the most common classes of small molecule biosynthesis systems,

• type I modular polyketides, 
• type II iterative polyketides, and 
• non-ribosomal peptides, 

says Brady.

The investigators used PCR to amplify collections of gene fragments from each of the three libraries and compared these to assess the similarities and differences between the collections of genes cloned from each environment, says Brady.

"Our work suggests that the genomes of environmental bacteria could encode many additional drug-like molecules, including compounds that might serve, among other things, as new antibiotics and anticancer agents," says Brady. "This is a small preliminary study that warrants additional investigations of more environments and more extensive sequence analysis, but it suggests that environmental bacteria have the potential to encode a large additional treasure trove of new medicines."