Daily Archives: October 19, 2013

In an advance that could help battle disease and create new biotech materials, researchers at Yale and Harvard universities have fundamentally changed an organism's genome for the first time.

The researchers developed a new genome for an e.coli bacterium by replacing one kind of codon a sequence of three nucleotides that regulates amino acids with another kind of codon. Scientists have previously replaced genes, but this is the first time that such changes have been across the an organism's genome, the complex blueprint of life.

The study is published in Friday's issue of the journal Science.

By recoding the genome, researchers say, the bacteria will be able to produce proteins that don't occur in nature, creating the possibility of new drugs and biotechnology materials.

For instance, the researchers say it could lead to the use of virus-resistant organisms in the biotech industry. Viruses use the proteins produced by the host organism, such as a bacteria, to infect cells, but doing this requires that the virus and host have the same genetic sequences. If the organism contains a new genetic code, the virus is rendered powerless because it can no longer properly produce proteins.

"By changing the code, we're establishing the fundamental proof of principle that they can be resistant to viruses," said the paper's co-senior author, Farren Isaacs, assistant professor of molecular, cellular and developmental biology at Yale. George Church, professor of genetics at Harvard Medical School, is the study's other senior author.

By using organisms with recoded genomes, Isaacs said, biotech companies could stave off the kind of havoc that a single viral infection can cause. For instance, Genzyme, a Massachusetts-based biotech company that shut down for three months and suffered up to $1 billion in damages after a viral contamination.

"If you could use a genetically recoded organism, it could mean a striking decrease in the rate of viral infections," Isaacs said.

The research could also potentially allay fears about genetically modified organisms, he said, because the recoded organisms would be unable to infect natural organisms in the wild.

Brenton Graveley, professor of genetics and developmental biology at the UConn Health Center, said the research could have "profound possibilities" for synthetic biology the field of creating new organisms through genetic manipulation.

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Yale, Harvard Scientists Change An Organism's Entire Genome

Youve heard of decoding the genomethe monumental scientific project to learn the blueprint of a human being by reading the DNA book of life, letter by letter. Over the past few years, scientists have been making quiet progress on a less-publicized effort to recode the genome, by developing powerful tools that will allow them to edit or completely rewrite it on a massive scale.

When trying to understand why thats important, the powerful book of life metaphor unravels a little bitafter all, what would be valuable about taking a finished work of Shakespeare and swapping in synonyms or completely new words at various spots in the text? Its hardly likely to enrich the experience of reading a classic play.

To understand why it matters, one has to think about DNA more like an engineer trying to build new things. The four letters of DNA are strung together in three letter words, each of which makes an amino acidcompounds that cells combine to make proteins. Swapping out letters or words therefore means that scientists can create whole new organisms that manufacture novel kinds of proteins that might have industrial or biomedical uses.

Its expanding the chemical repertoire, said Farren Isaacs, assistant professor of molecular, cellular, and developmental biology at Yale University. By making these fundamental changes to the code, you can create organisms that are safer,... more useful for the biotechnology industry, and organisms with alternate genetic codes are actually resistant to viruses.

On Thursday in the journal Science, Isaacs and George Church, a biologist at Harvard Medical School, reported in a pair of papers on new efforts to advance a technique developed a few years ago that enables massive editing of the genome.

In one paper, the researchers were able to replace several hundred instances of a particular sequence of three letters in E. coli with a different sequence that essentially instructed cells to create the same proteins. That meant the bacteria could still function. Then, they inserted a novel sequence, creating a bacteria that could create a protein not found in nature. They were able to show that these changes also made the bacteria resistant to viral infections.

In a second paper, the researchers were able to show the scope of genetic words they could tweak, not limiting themselves to a single sequence of three letters.

There have been a number of methods pioneered over the past few years to edit the genomes of organisms, giving biologists a large tool kit. Isaacs and Church used a technique that makes targeted changes to DNA and also takes advantage of the process of evolution to select the strains of altered bacteria that are most viable.

There are different ways to skin the cat, Isaacs said. Its pretty exciting right nowwere suddenly in the past few years seeing this influx of new types of technologies that are allowing us to perform unprecedented changes to genomes, and thats really exciting and powerful.

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Re-coding the genome

Harnessing the power of genome sequencing could have a "really tremendous impact" on cancer testing and treatment, says Nazneen Rahman of the Institute of Cancer Research and the Royal Marsden Hospital.

Speaking at Wired 2013 in London, Rahman who is a geneticist and doctor specialising in disease gene discovery, cancer predisposition and clinical genomics explains that she wants to make genome evangelists of us all. We should sit up and take notice, because she says we all have the ability to develop cancer -- "cancer has no respect for age or gender, race or ethnicity, wealth or class".

"Our genomes are both beautifully simple and unfeasibly complex," she says. They consist of the three billion letters of code, inside which are stored the instructions for how our cells divide. Looking for a mutation in the code has up until now involved combing laboriously through it.

A new process though, means you can break up the code into millions of fragments and read them all at once. Rahman describes this as "an all-bets-are-off, anything-is-possible kind of change" that has vastly changed the potential of what scientists are able to do in all areas of medicine.

To discover the mutations that have caused cancer in people, doctors used to have to look down the microscope, but now they can just look at the genome and trace the path of the mutating code. Similarly, chemotherapy used to tackle all fast-dividing cells, but we can now make a specific targeted drug that only tackle the mutating cells.

The same tactic can be used to identify mutations that are passed down through generations which means lots of people in the same family are affected by the same cancer. Using the old process for combing through genetic code for hereditary mutations was so time-consuming and difficult that it's very expensive, and therefore only available to the super rich. If we adapt the new changed in genome technologies though, says Rahman, we can make genome testing an affordable possibility for everyone.

In looking for mutations, one of the challenges is that our genomes are littered with mutations -- some of which are dangerous, some of which aren't -- but misinterpretations rather than helping people, can end up doing harm. To avoid this, more people will need to be sequenced, because the more data you put into a system, the better interpretations you get out of it. "This is an area where big data is going to be a big help," she says.

In order to have a way that doctors can routinely use these tests, we need to make sure tests are accurate, but also that people are educated about sequencing and have confidence in the process. This is why we all need to be genome evangelists, but, she adds "we do have to be cautious evangelists -- if that's not a contradiction in terms."

Read more from Wired 2013's incredible spread speakers, thinkers, innovators and thought-leaders in our Wired 2013 hub.

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Nazneen Rahman on why she wants to make genome evangelists of us all