REPOST: A new opium pipe

Christina Smolke and her colleagues at Stanford University are working on a synthetic process for the cultivation of opium poppy, which is essential for the production of opiates. If their experiment proved successful and the production procession commercially viable, will become a non-protein medicine that can be made by biotechnology. Read more about their work in the following article from The Economist.

SYNTHETIC biology—the technique of moving genes from creature to creature not one at a time, but by the handful—promises much but has yet to deliver. Someone who believes it can, though, is Christina Smolke of Stanford University. And, as she and her colleagues write in Nature Chemical Biology, they think they now know one way that it might.

 Image Source: economist.com

Opiates, such as morphine, are widely used as painkillers. Some are extracted directly from opium poppies (paler, as the picture shows, than the sort familiar in Europe and North America), which grow well in places such as Afghanistan and Turkey. Others, such as oxycodone, are chemically derived from natural poppy-molecules. Many of these drugs, though, are also used for recreational purposes—particularly diamorphine, an acetylated version of the principal poppy extract that was branded “Heroin” by its manufacturer, Bayer, in the late 19th century. Since such recreational use is generally illegal, the authorities keep a strict eye on the opium trade, and would no doubt welcome the chance to make that eye even stricter by cutting poppies out of the loop and making diamorphine and its cousins from scratch in facilities they can watch. That, plus the possibility the drugs might be produced more cheaply, has encouraged Dr Smolke to use synthetic biology to see if she can create an alternative source for opiates.

To do so, her team added three crucial poppy genes to some yeast cells. When provided with the appropriate chemical precursor, the modified yeast cranked out morphine and another opiate, codeine. And when one of the poppy genes was itself replaced by two genes from Pseudomonas putida, a soil bacterium, the yeast made oxycodone and hydrocodone too. Though this prototype yeast was not particularly efficient, some further tweaking converted it into a veritable drug factory—capable of cooking up 131mg of opioids (the equivalent of about 26 medical doses of diamorphine) per litre of culture over a four-day manufacturing cycle.

Single spies v battalions

The idea of using genetically modified micro-organisms to make drugs is not new. Mostly, though, those drugs are “biologics”—in other words, proteins for which no standard chemical synthesis is possible. Such biologics include erythropoietin (which promotes the growth of red blood cells), human growth factor and insulin. The modification needed to create a biologic is the addition of but a single gene, namely the gene for the protein in question. The micro-organism’s natural protein-making machinery will then do the rest. Such single-gene transfers are not normally counted as synthetic biology.

Conversely, some drugs—penicillin, for example—are the natural products of unmodified micro-organisms. The pathways that make these non-protein molecules have many steps, sometimes dozens, each controlled by a particular enzyme. What Dr Smolke has done is to assemble appropriate pathways by transferring the genes for each of the enzymes involved.

The job is not yet finished. At the moment, her modified yeast has to be fed with a precursor chemical called thebaine, and this still has to be extracted from poppies. She is, therefore, now trying to coax some yeast into producing thebaine as well. She is nearly there. In previous work, published in 2008, she engineered yeast capable of synthesising a molecule that was two steps removed from thebaine.

If Dr Smolke succeeds, and the technology is commercialised, opiates will join an antimalarial drug called artemisinin as non-protein medicines that can be made by biotechnology. Natural artemisinin is extracted from a species of wormwood that grows in China. The synthetic sort is made by Sanofi, to a recipe devised by Jay Keasling, a researcher at the University of California, Berkeley, and developed by Amyris, a firm he helped to found. And there may be a third drug in the pipeline.

Earlier this year a group led by Bradley Moore of the University of California, San Diego, transferred a cluster of bacterial genes which they suspected might encode the pathway for making an unknown antibiotic into another bacterium, Streptomyces coelicolor. They were right. Their discovery is called taromycin A. In a world crying out for new antibiotics, as bugs develop resistance to old ones, this may prove an important find. And if taromycin A does fulfil its promise then, thanks to Dr Moore, a biofactory that might be used to make it is already up and running.

Businesswoman and environmental advocate Janique Goff supports start-up businesses in the biotechnology industry. Read more related stories on biotechnology and pharma research here.

REPOST: Biotechnology: The start-up engine

A company composed of biotech elites, Third Rock Ventures took risks as they ventured the industry of biotechnology. Find out how the Boston-based company gained success in this article from Nature.com.

Bioengineer Mikhail Shapiro got a rude shock one day when he arrived for work at Third Rock Ventures, then a brand-new venture-capital firm headed by a handful of biotech elites. Only three weeks into his internship, Shapiro found a notice on the door: “Closed for business.” Inside, 'For sale' signs hung on desks, equipment, everything — even the office's giant gumball machine. The company had folded, a note explained, because it could not raise enough money.

Kevin Starr (right) and Mark Levin founded one of the hottest venture-capital firms in biotechnology.
Image Source: www.nature.com

Kevin Starr, a partner at Third Rock, still beams with pride over that 2007 prank, which he and his confederates had filmed to capture Shapiro's reaction. “You could tell Mikhail was thinking, 'I knew that was going to happen to these guys!'” he recalls.

Few would fault Shapiro, now a professor at the California Institute of Technology in Pasadena, for his credulity. By 2007, the technology bubble of the early 2000s had burst, and investors were baulking at the long timelines and high failure rates involved in getting biotechnology products to the market. People laughed, says Starr, when he and Third Rock's other founders told them that the company wanted to raise US$378 million to create an investment fund to build biotech companies from scratch. “They advised us to aim for about a tenth of that.”

But Third Rock, based in Boston, Massachusetts, did raise its initial fund, and it has not slowed down since. The company has brought in $1.3 billion and invested in more than 30 young companies, many based on cutting-edge research in fields such as cancer epigenetics, gene therapy and medical diagnostics (see 'Due diligence').

Image Source: www.nature.com

Products are only just starting to trickle out into clinical testing, but this year brought several signs that the firm has bet well. In January, Third Rock sold off Lotus Tissue Repair — a tissue-engineering company with an experimental therapy for a devastating rare disease that weakens skin. The deal could garner a 20-fold return for Third Rock if Lotus meets certain milestones. In March, Third Rock's third round of funding — $516 million to launch up to 16 more companies — had so many aspiring investors that the firm had to turn some away. And this summer, two of Third Rock's companies went public, their share prices soaring the moment they hit the market. As Nature went to press, a third firm — cancer diagnostics company Foundation Medicine in Cambridge, Massachusetts — was preparing to follow suit.

“For a long time, people said investing in these early-stage companies was not a great idea,” says Robert Langer, a bioengineer at the Massachusetts Institute of Technology (MIT) in Cambridge who has spun off dozens of companies from his research (see Nature 458, 22–24; 2009). “Third Rock has taken that risk and I think it's paying off.”

Laid-back biotech

Since 2007, Third Rock has expanded its offices on Boston's trendy Newbury Street — a neighbourhood filled with high-end boutiques and cafes. On a flaming day this summer, Starr sits in his office arrayed in silver jewellery, camouflage shorts and a green T-shirt that reads “Beach Punk 1982”. A standard business shirt bides its time on a hanger behind the door.

Starr's laid-back style has found lots of attention in the business press, and it serves as a reminder that he does not have to be here. In 2003, he left a post as chief operating officer of Millennium Pharmaceuticals, a Cambridge-based biotech powerhouse that had just launched the blockbuster cancer drug Velcade (bortezomib). Millennium founder Mark Levin retired some time after Starr, and the two did the usual things that young retirees with plenty of money do — travelling the world and producing independent films and Broadway shows. In 2006, Starr says, during an annual pilgrimage to the golf courses and blackjack tables of Las Vegas, Nevada, Levin turned to him and said, “Hey Kev, why don't we just go do something again?”

Venture capital has a pivotal role in transforming science into medical advances, supporting companies during the long, lean, research-intensive years before they have any hope of turning a profit. In the United States, biotech soaks up billions of dollars in venture capital each year, second only to the software industry. In the mid-2000s, infusions into fledgling companies made up just a tiny fraction of that investment. Most of the money was going to established companies, often with products already in clinical testing. But the pharmaceutical industry was tightening internal research budgets and looking to small biotechnology firms for new medicines.

Amid that changing landscape, Starr and Levin saw an opportunity. There would be demand for innovative biotechnology companies, yet few venture capitalists were in a position to fill it. Through a series of meetings at Starbucks, Levin and Starr assembled a skeleton crew of biotech nobility and mapped out their ideal venture-capital firm.

Standing out

Levin, Starr and Bob Tepper, former head of research and development at Millennium, wanted to do things differently from typical venture capitalists, who sift through ideas and business proposals from external researchers, help to set up a company and then hand over control to a newly recruited executive team. Starr says that he and his co-founders wanted to recreate some of the magic they had felt at Millennium, carrying over its 'anything is possible' mantra. They would hire only the best people, even if that meant interviewing candidates for months. And, rather than relying on proposals from the outside, they would focus on the hottest science, mostly investing in companies conceived by Third Rock's team. “Last year we saw 982 outside plans,” says Starr. “We invested in zero.”

All venture capitalists need to understand the science behind their investments, but Shapiro, who has since worked with other venture-capital firms, says that Third Rock is unique in how far its members personally immerse themselves in the details. “It's a bunch of nerds,” he says. “You're in a commercial setting, but the rigour of the science was as high as it was at MIT or Caltech.” Of the more than 40 employees now at Third Rock, only Levin, a chemical engineer by training, had worked in venture capital before. The rest had trained in the trenches as scientists, physicians and biotech business leaders. “They have decades of real, hands-on experience,” says Michelle Dipp, a venture capitalist at the Longwood Fund in Boston. “It's an incredibly talented team.”

Third Rock also takes its time handing over the reins of its companies to outside executives; it often waits 18 months or longer. That is important for luring top talent, says Langer. “A lot of good chief executives are not willing to take the risk with a new company,” he says. “With Third Rock, rather than getting the company when it's a newborn baby, a new executive is getting a pretty active 2-year-old.”

Finding newborns to raise means exploring promising ideas, something that Third Rock spends about one-third of its time doing. Those that pass muster get up to $2 million and must go through a rigorous and lengthy screening process that employees refer to as the 'Third Rock Ultra Killer Kriteria' (TRUKK). Independent labs must be able to replicate key findings and find no warning signs of toxicity for drug candidates.

A San Diego, CA-based business development manager, Janique Goff is a supporter of environment-friendly technologies and projects. She has been promoting companies involved in biotechnology for several years now. More links to related articles can be found on this Facebook page.