Manufacturing plant: The little green alga Chlamydomonas reinhardtii can be engineered to produce proteins for use in therapeutic drugs.
Beth Rasala, UCSD
Algae could provide a cheaper, easier method for manufacturing drugs.
Green algae are cheap to grow, hard to kill, and quick to thrive. Such traits make the tiny plants an ideal production factory, one that is already being extensively explored as a source for biofuels. But a few people are also looking to algae to do a completely different brand of work: the manufacturing of therapeutic drugs, a system that could one day produce large quantities of certain drugs at one-thousandth of today's costs.
A huge number of so-called biologic drugs, made up of proteins rather than small molecules, are produced, en masse, by bacteria, yeast, or mammalian cell culture--the cells produce proteins that are processed and turned into therapies for cancer, multiple sclerosis, and diabetes, among many other diseases. But such methods can be expensive to set up and maintain: Feeding them requires large amounts of nutrients, sustaining them requires large amounts of energy, and creating sterile facilities is a costly proposition. Stephen Mayfield, director of the San Diego Center for Algae Biotechnology at the University of California at San Diego, believes that algae, which subsist on sunlight and carbon dioxide in the air, could be an ideal and cost-effective substitute.
In a paper published in the Plant Biotechnology Journal, Mayfield and his colleagues looked at the versatility of the green alga Chlamydomonas reinhardtii in order to determine whether it had the potential to act as a robust drug factory. They inserted genes for production of seven different therapeutic proteins currently being made in yeast, bacteria, and mammalian cells, including interferon (for multiple sclerosis) and proinsulin (for diabetes). Of the seven, the algae produced four proteins at levels high enough for commercial use and in forms that were identical to those made by bacterial and mammalian cell systems, and are just as easy to isolate and concentrate.
Complicated proteins that are produced in mammalian cell culture, such as the potent multiple sclerosis drug Tysabri, currently cost an estimated $150 or more per gram of protein. (The number is estimated because few companies release such statistics.) In green algae, Mayfield says, it's closer to a nickel. "That's because it's a plant and it grows in minimal media, pulling carbon dioxide out of the air and using sunlight for its energy source."
In addition to producing drugs more cheaply, algae plants are cheaper to build. Startup costs for mammalian cell culture plants are the "biggest bottleneck in developing new protein therapeutic drugs," says Mayfield. "Clinical trials are expensive, but before you even get to the clinic, you have to invest $600 million to build a facility to produce it."
ExxonMobil invests $300 million in Synthetic Genomics to develop algae biofuel.
OriginOil claims that its technology extracts oil from algae cheaply and efficiently.
Manufacturing in the United States is in trouble. That's bad news not just for the country's economy but for the future of innovation.
Our list of the 50 most innovative companies, including the following:
On Twitter
Become a Fan on Facebook
Subscribe to the Feed
anonalgae
1 Comment
Why?
Upstream production cost is not the limiting economic factor for biologics. Moreover, if not secreted how much more will the downstream cost be vs. mammalian to get to purified ai? Net manufacturing cost will likely not be much improved. Then there is the regulatory risk of a new platform with unknown contaminants, etc. Taking these factors together, any non-standard manufacturing system has to be able to offset these disadvantages with unique PK or PD advantages it confers on the drug substance or it will be a non-starter even if many times cheaper to produce.
Reply
erbium
340 Comments
Re: Why?
Mammalian cell production introduces possible contamination with biologically active molecules that can specifically affect mammals (i.e. the end users of the medicines, people or farm animals). Or viruses, and mammals can't be grown in vats, and mammalian cell cultures take more expensive specialized nutrients so yields are much lower. You can't assume the value of any compound is so much that the huge expenses and long lead time of producing in mammals or mammalian cell lines can be justified.
Recently show on ocean drugs featured biochemist who collected algae from mangrove swamps in panama. His take is that algae are amazing biochemical factories. In this case he was searching for new compounds they already produce for daily living to utilize sunlight or fend off biological competitors, predators or parasites, not to insert genes into.
They can synthesize compounds via routes that mammal biochemistry cannot. They can synthesize compounds that would be toxic to mammal cell lines during production, or whose intermediaries would be toxic even if end product is a medicine.
In fact it seems that pretty much ANYTHING is better than mammalian cell lines for production of complex chemicals, for reasons mentioned in the article and one of the bases for this is that organisms such as yeast have a vastly more complex set of chromosomes. Yes, we have a wimpy set of chromosomes despite the ability of our genes to produce sentience in us. Yeasts just pack in dna in huge amounts allowing it to synthesize all sorts of stuff. I'm only guessing but algae is probably similar in ability.
Reply
moo
1 Comment
Re: Why mammalian cultures are still indispensable
Two words: protein folding
Reply
erbium
340 Comments
Protein folding
maybe they'll find that certain mammalian genes can be inserted into algae to produced the protein folding needed.
(insert quite a bit of research and time here)
Reply
lgravitz
5 Comments
Re: Why mammalian cultures are still indispensable
Actually, many mammalian-cell produced proteins have to be re-folded in a post-production process in order to get them into the right configuration for use in human drugs. Algae, on the other hand, can fold some of these proteins correctly the first time around, saving cost on the post-production end of things.
To get jargony, algae are eukaryotic cells, so are quite capable of complex protein folding. According to researchers involved with the project, as well as outside sources, the major issue is one of attaching the right sugars (glycosylation). And since some therapeutic proteins don't require glycosylation, that's where the researchers are focusing first.
-Lauren
Reply
pharmguy
2 Comments
Re: Why mammalian cultures are still indispensable
Actually, its bacterial expression that often requires refolding. Mammalian expression does not - in fact, it is much simpler to correctly express complex, disulfide bonded proteins in mammalian cells than it is in other systems. Algae chloroplasts can do this in a very limited way, but the big problem is purification. The cells have to be broken, and the protein products have to be separated from all the sticky cell contents. Not trivial or inexpensive. In fact, it can be much more costly than the actual cell-based production. In contrast, mammalian cells secrete proteins into the medium making purification much more straightforward. Modern mammalian culture systems can use disposable bioreactors to reduce contamination and carry-over (and eliminate clean in place costs and much of the validation expense). Algae have an enormous bar to cross, and cost of goods alone doesn't begin to accomplish this. The plant production folks went down this road 10 years ago, and where are they now? Any alternative expression system needs to have a really good, product-focused rationale if it is going to succeed. This seems like just one more grandstanding professor (and of algae, not even biochemistry - I just looked him up) who knows little about the real world of pharma.
Reply
pharmguy
2 Comments
Re: Why?
Please realize you are confusing small molecules with recombinant human proteins. Algae certainly can do some interesting biochemistry, and no doubt there is bioactivity there to be tapped. However, the focus of this work is using algae as a bioreactor for recombinant proteins of human (ie mammalian) origin. For those, mammalian cells are unequivocally the gold standard for bioproduction. Costly, of course, but still the best way to go for fidelity and activity.
Reply