By Harnessing the potential of synthetic biology on Feb 23, 2022 04:32 am
Synthetic biology is not a new thing. For our benefit, we have been manipulating organisms genetically for decades now. For example, recombinant insulin was first made in 1978 by inserting the human insulin gene into E. coli.
What’s new, however, and what deserves to recast the traditional methods of genetic engineering into the new field of synthetic biology are the following trends:
- Rapid decline of cost of DNA sequencing (and DNA synthesis).
- Explosion of biological data
- Because of decline in sequencing costs, we have more types of biological data from more number of species than ever before
- Rising sustainability concerns
- Increasing concerns about dependence on animals or chemical means to make products, which is causing a strain on our environment.
- Biological production uses less energy/water/land and typically makes products that are biodegradable
Today, it’s cheaper and easier than ever to engineer a cell to make the desired molecule. That’s why synthetic biology deserves to be called as genetic engineering 2.0
Harnessing nature to make useful things
Out of all possible organic reactions, biology only uses a fraction of them. This should mean that it may be wiser to invest in organic chemistry than in synthetic biology.
However, all economically useful chemicals serve human needs and these needs tend to be mostly biological in nature. We evolved in an environment full of other organisms. Some of them make us sick, others make those organisms that make us sick, sick. Hence, rather than starting from the scratch and use chemistry to come up with something that serves our needs, it may be useful to survey the rich biodiversity for a solution that nature may have already found.
The fact that we’re embedded in nature that shapes our needs pushes us to find solutions from the nature itself. Hence, practically, it is likely that for a problem we want to be solved, harnessing nature is a better bet that searching for the vast space of possible molecules.
Another reason to look towards biology for making useful things is because biological organisms, unlike synthetic chemical reactions, operate at ambient temperatures and produce fewer or none toxic byproducts.
Basics of synthetic biology
The basic process of synthetic biology is pretty simple:
- With a problem at hand, define what an ideal solution will look like
- E.g. in case of diabetes, a shot of insulin is what’s needed
- Search in nature what organism (or a set of organisms) produces the exact desired product or the closest analogue
- Copy the genetic instructions from the discovered organism into a host cell that you can grow in a bioreactor
- Copy insulin gene into E. coli.
- Tweak the genome of the host cell to maximize production of desired product
- Add multiple copies of the gene
- Generate variants with mutations to screen for highest insulin producing variant
- Delete non-essential genes to prevent redirection of cellular resources
- Once the desired production yield is achieved in a lab, scale the process to produce the desired molecule in large bioreactors
- Purify the mixture to isolate the molecule of interest from cell debris or unconsumed media
Doing the steps listed above is not hard. There are now kits to do synthetic biology at home. In fact, easy production something as important as insulin is also being pursued by an open source group.
The central challenge of synthetic biology: yield of the desired product
While it’s likely that many of the products that we desire can be found in nature, it’s often not enough in quantity to satisfy our needs. Organisms have had no evolutionary pressure to optimize yields of products that humans find desirable.
Because organisms naturally produce useful many beneficial chemicals, it’s relatively easy to make the desired product in principle at a lab scale. However, the challenge really is producing it in enough quantities so it’s economically feasible. And that requires maximizing the concentration of desired product per unit volume of inputs (mostly growth medium) and per unit of time.
The less the concentration of the desired product, the larger the bioreactor / production process will have to be and the more expensive will the production be.
So, it is recommended to calculate the target yield of the desired product at which economics will make sense. Only scale the production volumes to pilot or larger scales if the target yield has been achieved on a lab scale.
Economics of synthetic biology
At the simplest level, economics of synthetic biology for non-pharma applications works as follows:
Profit ~ (Price of end product - Price of growth medium) * Yield of end product
The higher the price differential between growth medium and end product and higher the yield of product per unit of growth medium, the higher will be the profit.
For pharma applications, cost of regulations/compliance and R&D from failed projects dominate the cost. So we can approximate profit as
Profit ~ Market size * Probability of approval
For pharma, even though the purity required in end products is >99.95% which drives up the cost of production, the final cost is still dominated by clinical trials and approvals. Like I wrote in Why brain-machine interfaces progress so slowly, getting an approval for medical applications could take years and millions of dollars. This is why pharma is dominated by large corporations who have this kind of patience and investment apetite.
Economic considerations as the key driver of synthetic biology’s potential
The decade of 2000-2010 was hailed to be the one of biofuels. The idea was to use yeast to produce ethanol (like it does for beer) but use the ethanol as a substitute for petroleum or diesel. Biofuels were supposed to be the biggest application of synthetic biology to date.
But, today, a decade later biofuels industry is more or less dead. And the reason for that is simple: crude oils became cheaper.
Look at the graph above. The enthusiasm for biofuels was driven by the rising oil prices that started from 2000. But the sudden crash of the prices in 2008 made crude oil much more competitive than biofuels (which has remained as the case even until today).
In addition to crude oils getting cheaper, new renewable energy alternatives that emerged from solar and wind technologies made biofuels look inferior in comparison.
I think biofuels hold an important lesson for synthetic biology. It’s that economic considerations trump everything.
Intellectual Property in Synthetic Biology
According to the prevailing patent laws in the US, you can’t patent a naturally occurring gene or a bioproduct. However, you can patent artificial modifications to the gene/bioproduct that enhances the function in some way.
As seen in the section above, most naturally occurring bioproducts aren’t optimized for human use. They need tweaking and optimization to increase yields, reduce toxicity, enhance functionality. This means, practically, patents are strong barriers to entry in the synthetic biology world.
Take the case of insulin. The first insulin via genetic engineering was produced in 1978. Since patents have a life of 20 years, it should have gone off patent three decades ago and we should expect the market to be flooded today with genetic versions of insulin from many commodity brands. Yet, the insulin market is cornered by three large pharma companies and is super-expensive as a result.
The reason behind this is the continuous improvement of insulin and its delivery characteristics by these pharma companies. Via various optimizations,these companies have made insulin slow-releasing and more effective than the native insulin made by E. coli expressing the unchanged human gene for insulin. They have patented these improved versions and hence there’s no competition for the improved versions.
Sure, anyone can make the off patent insulin of 1978 (and some volunteers are trying to do in open source fashion). This much-cheaper version will probably be useful to many who can’t afford the expensive improved one. But what prevents this from happening is the requirement by agencies like FDA to prove biosimilarity of these cheaper generic versions to the originally approved insulin. Proving similarity for small molecule drugs (like asprin) is easy and cheaper. But synthetic biology products (like insulin) are made by microorganisms and they’re never exactly the same.
So FDA has a much more stringent criteria to approve generics made from biological cells than for chemically synthesized generics. This additional cost of regulation for an off-patent product disincentivizes production of old, off-patent synthetic biology products.
For pharma/medical applications, the cost of regulations dominates the economic considerations and hence ultimately is the deciding factor for whether a synthetic biology product will become a reality or not.
Conclusion
Yes, synthetic biology may be full of potential but the products it produces compete in the market with traditionally but (economically) efficiently produced products.
So, either we need to use synthetic biology to produce novel and useful products that don’t yet exist OR if we are replacing an existing product using biological means, we need to make sure it is of lower cost and higher quality than what’s available today.
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