Synthetic biology for drug manufacture

For years now, I have been expecting people to use synthetic biology to make complex organic molecules like pharmaceuticals. If you splice the genes that allow some organism to make the molecule in question into another organism that is easy to cultivate, you can go from making the drug in a large and costly factory to cultivating it in a cheap batch of genetically-modified yeast.

This is now being done: Genetically Engineered Yeast Makes It Possible To Brew Morphine, A Way to Brew Morphine Raises Concerns Over Regulation, An enzyme-coupled biosensor enables (S)-reticuline production in yeast from glucose.

Author: Milan

In the spring of 2005, I graduated from the University of British Columbia with a degree in International Relations and a general focus in the area of environmental politics. In the fall of 2005, I began reading for an M.Phil in IR at Wadham College, Oxford. Outside school, I am very interested in photography, writing, and the outdoors. I am writing this blog to keep in touch with friends and family around the world, provide a more personal view of graduate student life in Oxford, and pass on some lessons I've learned here.

13 thoughts on “Synthetic biology for drug manufacture”

  1. Scientists, at least those who aren’t arachnophobes, have tried to mass-produce spider silk for decades with little success. Spiders are territorial and cannibalistic—try to farm them, and they end up eating each other. But scientists have long believed that if spiders would only cooperate, fabric made from their silk would be well-suited for use in military and medical equipment, like wound sutures or artificial tendons, as well as in high-performance athletic clothing and other garments.

    Instead, the researchers genetically engineered yeast to produce the same material through fermentation.

  2. Newly Risen From Yeast: THC

    In August, researchers announced they had genetically engineered yeast to produce the powerful painkiller hydrocodone. Now comes the perhaps inevitable sequel: Scientists have created yeasts that can make important constituents of marijuana, including the main psychoactive compound, tetrahydrocannabinol, or THC.

    Synthetic versions of THC are available in pill form under brand names like Marinol and Cesamet; they are generally used to treat nausea, vomiting and loss of appetite caused by H.I.V. infection or cancer chemotherapy. Genetically modified yeast could make THC in a cheaper and more streamlined way than traditional chemical synthesis.

  3. “Both yeasts rely on so-called precursor molecules — not simple sugars, which would be ideal — and can produce only small amounts of THC and cannabidiol. But Oliver Kayser, a biochemist at the university, hopes that he can eventually engineer the yeast to replicate the full THC-production pathway and has teamed with THC Pharm of Frankfurt to try to scale the processes for industrial production.”

  4. Harvard scientists to make LSD factory from microbes

    Simple microbes such as those found in baker’s yeast can be modified to make LSD, suggests research by Harvard scientists

    Around 20 tonnes of lysergic acid, a precursor of LSD, are made each year and turned into real medicines, such as nicergoline, a treatment for dementia. The drug is purified from big vats of fungus (which make the compound naturally) using technology developed decades ago.

    With the tools of synthetic biology, Wintermute thought they might do better. The ergot fungus takes lysergic acid and turns it into a huge variety of exotic molecules. They could mix and match biological pathways from different species of ergot fungus and make potentially new drug molecules. They might even come up with a next generation dementia drug.

  5. Genomatica, an established biotechnology firm based in San Diego, is experimenting with a cell-free system which produces 1,4-butanediol in this way from simple sugars. 1,4-butanediol is a small molecule that is used to make polymers such as Lycra. Generally, it is cheaper to manufacture molecules of this size using chemistry, rather than biology, but 1,4-butanediol is an exception. It is already made for industry with the aid of genetically modified E. coli. Genomatica’s system churns out the enzymes involved in this synthesis, creating an entire cell-free metabolic pathway—and one in which all the sugar is devoted to making the target chemical, rather than a percentage of it being creamed off to run a cell’s other biochemical processes. The firm has not yet put the system to commercial use, but has high hopes for it.

  6. The capacity and cost effectiveness of the yeast production route is limited – for now at least – by the complexity of the chain needed to produce the precursor molecules. At present simple-to-produce precursor molecules are a requirement.
    On spider silk, I understood that the molecules themselves can be produced but I thought that the material properties of the fibre arrangment were also an important feature and yeast doesn’t help with those steps. The commercial applications development is progressing – one company is using silkworms rather than yeast for this reason As they state, they are ” the only recombinant spider silk producer to publicly provide performance specifications on our recombinant spider silk’s strength and elasticity.”

  7. Incidentally, the Kraiglabs site points out some important byproducts issues with yeast routes that will need to be effectively addressed. I think the yeast route to producing molecules very interesting but am less enthused by it as a route to producing materials, except where the molecules produced are amenable to 3D printing.

  8. Also, based on BoltLabs own information, the process currently demands the use of foodcrops, though they are hoping to use non-feedstock in future, the agricultural so other aspects of the environmental load of such production (if widespread) may be high.

  9. In a paper published this week in Nature, Dr Romesberg and his colleagues go a step further, by describing how they have coaxed their bacterium into making proteins containing amino acids that are not found in nature. Each unnatural amino acid to be inserted is represented by a novel codon that includes one of the team’s synthetic bases. In other words, their bacterium can quite happily read an entirely new, human-created extension to the standard genetic code, and use the instructions to produce proteins that no organism naturally makes. The hope is that one day this method could be used to make new drugs, polymers or catalysts.

    They then inserted into their bacterium a gene (made from the four standard bases) that encodes a transport protein (found in Phaeodactylum tricornutum, an alga), which allows the bacterium to ship the new bases across its cell wall. In earlier work, the scientists showed that their engineered bug can incorporate the two artificial bases into its genome, and will happily copy DNA strands containing them when it reproduces.

    Three more steps were necessary, however, before the bacterium could actually produce the new proteins encoded by its novel bases. To make proteins, cells first transcribe a piece of DNA into another long polymer called messenger RNA (mRNA). As its name suggests, this is the stuff that carries production instructions to the ribosomes, the cellular factories where proteins are assembled. The team thus needed to make mRNA versions of the two synthetic DNA bases.

    As a next step Dr Romesberg hopes to extend the bacterium’s genetic vocabulary. The two new bases mean 152 more codons are available to represent non-natural amino acids. Proteins made with synthetic ingredients should be more easily tailored to have desirable therapeutic properties (to be longer lasting, for example, or more powerful) than the natural sort. Synthorx, a biotech firm based in La Jolla which Dr Romesberg founded in 2014, was set up to explore exactly such possibilities.

  10. In 2016 Frances Arnold, of Caltech, corrected nature’s deficit, using evolution to create an enzyme which stuck silicon to carbon and opened up a whole new realm of chemistry to biology. She now guides her directed-evolution technique, which won her a Nobel prize in 2018, with machine learning, the better to alleviate the watchmaker’s blindness. She believes that synthetic biology can in principle create enzymes for most of the reactions today’s chemists bring about with rare catalysts, high temperatures and pressures, or environmentally unfriendly solvents.

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