January 15, 2008 (Vol. 28, No. 2)
Specific Demands Will Drive the Evolution of This Device
Predicting the future is never easy, and hindsight often shows how wrong even skilled individuals can be at predicting just 50 years ahead. Thomas J. Watson, then chairman of IBM, made his famous prediction in 1943, “I think there is a world market for maybe five computers.” In most industrialized countries today, many homes have four to five computers—one in each room.
Charles Duell, commissioner of the U.S. patent office at the turn of the century, predicted in 1899 that the U.S. patent office would be phased out in a few years because, “Everything that can be invented has been invented.” By 1899, the U.S. patent office had issued 631,234 patents. Today the number of issued patents is almost eight million.
How did they get it so wrong? The answer in my opinion is that they tried to predict the future looking from the wrong direction. It is not about predicting how a device will be used in the future, nor how it will evolve. This is impossible.
Instead, it is about predicting what needs will exist in the future that will determine the course of evolution. At the time Thomas Watson made his prediction, the computer was mainly used for calculating ballistic tables for the military. Clearly the market for devices to tabulate artillery data is limited.
The other pitfall in predicting the future is assessing the rate of change. How can you predict when a technology will change? How do you know when the old way of doing things will be gone?
It took 100 years for the telephone to become established and available in almost every home and office in the U.S. It took just 10 years for the facsimile machine to become a routine means of communication. But just as we were getting used to including fax numbers on our business cards, the Internet came along, and within a few years, email practically did away with the fax machine entirely. Who could have predicted the rapid adoption of email?
Bhaskar Chakravorti, in his book The Slow Pace of Fast Change, comments on this odd phenomenon where a technology dominates for a long period of time despite the development of better alternate technology. Then suddenly an adoption avalanche takes place, and the old technology disappears almost overnight to be replaced by something often completely different.
Arthur C. Clarke, the author of 2001, A Space Odyssey, is sometimes known as the man who predicted the future. This justly deserved reputation is due to his uncanny ability to describe devices of the future, many of which have already become reality. One of his most famous predictions was the idea of geostationary communication satellites. This was back in the 1945. Modern life today without satellite communications is almost inconceivable.
I think that part of the reason for Dr. Clarke’s success is his ability to foresee the problems of tomorrow, both technical and societal, which then led him to predict appropriate solutions that would evolve in the future.
Looking at a specific device, whether it be a bioreactor or the home computer, we can more effectively speculate on its future embodiment by extrapolating on what made it evolve to what it is today and what demands will drive its evolution tomorrow. A needs analysis is also useful in understanding the shortcomings of current devices and helps in planning future development.
Change and innovation are not inevitable nor are they often incremental. In most cases, change happens almost overnight, and the old ways then seem unthinkable. Look at the cell phone. How did we exist without this constant connection to everyone else? How did we make presentations before Microsoft™ PowerPoint?
I think that we are poised for seismic changes. The steel, stirred-tank bioreactor has been the dominant technology for over 50 years. On a recent visit to the Science Museum in London, I saw the original bioreactor used for making penicillin. It was built in 1957, and I could not help but notice that it looked exactly like a stirred-tank bioreactor that you would purchase in 2007.
The requirements for a bioreactor in the pharmaceutical industry are now quite different from those 50 years ago. We need devices for patient-specific therapies, simple-to-use bioreactors for cell culture, and high-density perfusion devices to make red blood cells.
In the last 10 years, disposable bioreactor technology has taken the industry by storm. The benefits of this single-use technology are starting to accelerate the adoption of new instrumentation beyond the ubiquitous stirred tank.
As with all change, many people are uncomfortable with new ways of doing things. Most people try to cope with change by holding on to some familiar aspects of the past.
A good example is the development of the automobile. The dominant personal transportation mode at the onset of the 20th century was the horse and buggy. The automobile was disruptive technology. If you look at early automobile design, it looks exactly like a horse-drawn carriage with the horse missing. This horse-less carriage was not designed because it was technically necessary but because it was more familiar and therefore less threatening to the person comfortable with the horse and buggy.
In recent bioreactor design we see the same phenomena. Disposable bioreactors have demonstrated how inefficient, costly, and difficult to operate stirred tanks are. Yet, people are afraid to abandon their old beloved friend so easily. Hence, a number of disposable stirred-tank designs have sprung up to make them feel better.
Like the horse-less carriage, though, these steel-less tanks are transition devices and will be replaced by technology with better characteristics, as people get used to the fact that looking like a stirred tank is not a prerequisite for a good bioreactor.
The Look of the Future
Let us start with defining what a bioreactor really is. In a simplistic sense, it is a device in which some sort of controlled biological activity is carried out. The key phrase is controlled. A vat used to brew beer when operated correctly is a bioreactor. A fermenting garbage heap with no control is not, however.
With this definition, the design of a bioreactor depends entirely on the required functionality. A bioreactor for making beer requires temperature control but not absolute sterility. On the other hand, both are necessary in a bioreactor for stem cell culture. A septic tank is a bioreactor but it is certainly neither sterile nor temperature controlled.
Similarly, the bioreactor of the future will depend on the process requirements and the industry it is used in.
Let us next examine some of the key areas where bioreactors are used and examine the influencing factors in each area. In trying to understand and predict the bioreactor of the future, we must look beyond pharmaceuticals into the broader definition of bioreactor.
Reactors for Bulk Therapeutics
Bioreactors for the manufacture of bulk therapeutics have been around since the discovery of antibiotics. Early devices were stirred-tank, chemical reactors that were modified for sterile operation and to provide the necessary aeration and temperature control.
With the growing importance of cell culture in last 10 years, these reactors morphed into the familiar stainless-steel, stirred-tank bioreactors that dominate cell culture today.
Cost pressures on the pharmaceutical industry, however, have spurred the adoption of alternate technologies, especially the use of disposables. Such devices provide cell culture capabilities in easy-to-use plastic bags at a fraction of the operating and capital cost of stirred tanks.
The biologics manufacturing revolution is, however, sadly not due to major advances in bioreactor design and engineering. The average cell culture bioreactor is little more than a sterile container with aeration. Single-use technology has done away with the low value-added tasks of cleaning, sterilization, and validation as well as much of the complex and unnecessary automation. No real scientific breakthroughs, though, have been achieved in bioreactor performance.
The real revolution in cell culture for the manufacturing of bulk therapeutics has been the engineering of high-performance cell lines and expression systems and understanding media development. It is these advances that have brought cell productivity to the high levels we see today. Ten years ago, a mAb yield of 200 mg/L would have been worthy of publication. Today yields of 2,000 to 3,000 mg/L are routine.
The implications on bioreactor design are stunning; increasing productivity 10-fold made the required bioreactor volume shrink from 1,000 L to 100 L. This in turn makes disposable bioreactor technology practical for manufacturing.
The other factor changing the bioreactor landscape is the proliferation of a large variety of drugs. Instead of making tons of a single blockbuster drug substance in a dedicated facility, it is now more common to make smaller batches of many products in one plant.
So perhaps the days of 10,000 L bioreactors are numbered. The bulk biotherapeutic manufacturing facility of the future will have high-performance engineered cell lines cultivated in compact high-performance bioreactor modules.
What do these trends mean for therapeutic bioreactor design?
• Standardizing biologics production: It is extremely ineffective to develop a whole new operating methodology for each product. As biologics become commodities, the manufacturing facility will become a modular plant with standard components and processes. The cell line will be engineered to perform in the standardized plant, and the product will be engineered to use a standard purification scheme as much as possible. The challenge for bioreactor designers will be to develop devices that can be used universally, are simple to operate, and robust.
• Consequences of high cell densities and high-performance expressions systems: Aeration and temperature control will require new thinking. Developing effective cell retention will be necessary to maximize media utilization and cell productivity. The control challenges here include the development of a perfusion bioreactor with extensive sensor and feed control strategies.
• Microbial fermentation: For those who cut their teeth on microbial cultivations, providing oxygen and complex fluid rheology are worthy engineering challenges. In the last 10 years, we have neglected the development of microbial bioreactors in favor of eukaryotic cell culture. Hundreds of useful therapeutics, however, are still made using microbial fermentation because they are either impossible or uneconomic to produce with cell culture.
Augmenting Personalized Medicine
Patient-specific therapy is the new frontier for pharmaceutical research. Knowledge of the human genome and the ability to cultivate cells outside the body will require new types of bioreactors. Basic applications will include the development of single-use devices for autologous therapy. Some of these applications will require making a bioreactor device simple enough to be used at the bedside. This is an enormous bioreactor design challenge.
Delivery of genes by viral and other vectors has also not been as easy as originally thought. The efficiency of delivery is poor, with the bulk of the vector not reaching the intended target. This makes the required dosage high, which in turn increases the required bioreactor volume. Advances in gene delivery and bioreactor design will ultimately make personalized medicine practical.
Many of the cells used in cell/gene therapy grow on surfaces. The science of cell-attachment surfaces has advanced little in the last 20 years. Control of the attachment and detachment process is especially poor, which makes scale-up almost impossible.
New technologies using nanofiber surfaces show some promise in providing better cell surfaces. This could be an important development, as more research shows that the nature of cell attachment plays an important role in cell performance.
Another problem in the cultivation of human cells and organs is the need for a complex cocktail of nutrients, growth factors, and other chemicals. Current technology attempts to provide all the necessary factors in a defined media. This makes cell culture expensive and low yielding. The biology is poorly understood, and critical signaling factors may be missing or may only be produced in response to some external stimuli.
For the next generation of bioreactors, it will be necessary to step away from the current approach, which is one of monoculture that tries to grow one type of cell in isolation, to the next level where we must deal with populations. Controlling cell differentiation and maintaining equilibrium cell populations will be another huge challenge in bioreactor design.
• Development of organ and tissue culture bioreactors: These devices will need internal structures that in some way mimic vasculature to provide nutrients and remove metabolic products. Nanotechnology and self-assembling structures may prove to be the way to finally grow organs.
• High-density production of cells: The human body is remarkably efficient, producing 7×109 erythrocytes/day at a concentration of 2×109 cells/mL. This is about 100 times the capacity of the best bioreactor currently available.
• Bioreactors with better attachment surfaces for cell growth: The key feature for this application will be new techniques to attach and detach cells under complete control and with minimal damage.
• Bioreactors for the culture of difficult cells: New bioreactors need to be developed that can be used for the expression of cells such as astracytes and neurons. These reactors could be constructed so that they incorporate layers of feeder and stromal cells to provide the necessary growth factors. Perhaps even microbes can be incorporated into these reactors to present antigens.
Food and Drink Industry
Bioreactors for food and drink go back to antiquity. The first known records date back to Mesopotamia around 4,200 BC. A beer brewing vat was built by the Meux Brewery in London in 1795 that contained 860,000 gallons of beer. It is perhaps the biggest bioreactor ever. Even today beer brewing is done in enormous stainless steel vessels, some of which can be over 1 million liters in volume. Bioreactors for food production include the production of soy sauce, amino acids, sake, cheese, and on and on.
Food production is a huge area for the future of bioreactor design.
• Development of more efficient ways of making food and beverage products: Bioreactors will increase in sophistication to improve product quality, increase yield, and reduce costs. New technologies for continuous fermentation will replace the current batch-dominated approach.
• Engineered foods will become a reality: The current methods of protein production are hopelessly inefficient in terms of utilization of land, water, and nutrients. Already, much of animal production is farmed. This trend will continue to where animal protein will be grown in tissue culture and then engineered for texture and flavor. The idea of growing a chicken breast in a bag is not as farfetched as it might seem. In fact, the growing world population will make synthetic animal protein a necessity. Growing tissue at huge scale and at a price competitive with agriculture will be a tremendous bioreactor challenge.
• Major scale-up: With the world population expected to exceed nine billion by 2050, new ways of feeding the world will have to be developed. This will include the growing of new foods using algae, yeast, and other microorganisms. Bioreactors of a scale currently unthinkable will be needed. The Green Revolution in the 20th century changed agriculture to confound Maltusian predictions of population decline. Perhaps food production in bioreactors will change the landscape again.
Sustainability has become the latest buzzword ever since human-induced climate change is no longer just a theoretical possibility. It is clear that to maintain our current lifestyle, it is no longer going to be possible to have a single-use society. Much of our current waste is not recycled nor is much of it recyclable.
In the past, humans used nature as the ultimate recycler—wastes were discharged to streams where microbial action broke these wastes down and reintroduced them into the ecosystem in a form that could be reincorporated. With the large increase in human population and activity, however, we have simply overwhelmed the available natural systems.
The need for treating waste is not new—almost all sanitary waste produced in the developed world is now treated in some fashion before it is discharged into natural waters. Without this treatment, all the rivers and lakes would have long ago become poisonous anoxic ponds of sewage.
The treatment of sanitary wastes is done in bioreactors. These are currently aeration ponds that oxidize the waste into a more innocuous sludge. We need to develop technologies to better utilize this waste and also to expand treatment to household and other waste streams.
Even the basic function of trees to recycle carbon dioxide from the atmosphere into oxygen seems to have been overwhelmed by our carbon output. Exciting new progress is being made using Archea microbes. A company called Greenshift (www.greenshift.com) has developed a membrane bioreactor using blue-green algae that can scrub carbon dioxide from flue gas producing oxygen and water byproducts.
With the ubiquitous production of plastics, we have now created a new class of waste that nature does not yet know how to digest. While biodegradable plastics are advertised, careful research has shown that even these materials are simply just broken down into smaller particles. The particles themselves are not broken down into elemental hydrocarbon building blocks that could be recycled into the ecosystem. For this we must wait for a few million years for nature to evolve suitable microorganisms.
Just as we discovered how to make these magical polymers from the fossilized remains of primeval forests, though, perhaps we can also learn how to use the versatile microbe to degrade these back into a usable black goo.
• Development of bioreactors to generate energy and other usable products from human, animal, and crop waste streams: Rural economies were well equipped to recycle waste products. New technologies need to be developed to provide the same disposal and recycling capabilities in an increasingly urban world.
• Development of robust and low-cost bioreactors for waste treatment and recycling: Robustness is a key challenge as failure of waste treatment often results in catastrophic consequences. Think about the robustness of a bioreactor that many of us have in our backyard—the septic tank. It is a mixed population bioreactor that can handle varying waste loads and composition without much if any interaction.
• Development of microbial bioreactors for the degradation of plastic materials: New knowledge of organisms such as the Archea demonstrate the potential for mixed microbial populations to degrade and neutralize many toxic and inert substances. The bioreactor challenges are immense, as we will need to control heterogeneous populations of microbes in reactors that may operate at high temperatures and pressure. These reactors may be the only way to handle the vastly varying waste streams of our industrial society.
• Bioremediation: Already, hundreds of applications are available using microbes to purify toxic wastes, leach-out heavy metals, and even deal with radioactive materials. Treatment of carbon-rich streams will require novel bioreactor design and microbiology.
Fuels and Energy
It is abundantly clear that global needs for energy are increasing. Yet, the production of the primary source of energy, crude oil, has peaked and is steadily decreasing. It is projected that the production of oil will drop to half its current level by 2020.
New sustainable sources of energy must be developed. In the biofuels area, ethanol has received much press coverage. Ethanol, however, is perhaps not the optimal solution. The cost of making ethanol is high, and there is even some controversy over whether making ethanol actually results in a net energy gain. The raw materials for ethanol must be grown specially, reducing availability for food crops, the fermentation is slow, and the organisms used are centuries old and could be optimized. Also, concentration of ethanol requires huge amounts of energy.
Optimal production of crops for biofuel can produce 6,000 bbls/square mile. To replace the world requirement for petroleum with biofuel crops would require twice the total farmland available in the world.
The field is ripe for revolutionary bioreactor technology using new organisms such as algae that have low nutritional needs and can use waste products as substrates.
• Optimizing the production of ethanol for biofuels: This requires the use of waste crop substrates. It requires genetic engineering of microbial species and development of bioreactor designs that can produce large quantities of high-concentration ethanol perhaps using continuous fermentation techniques coupled with membrane-separation technology.
• Algal bioreactors: Development of fuel farms where algal bioreactors produce biodiesel from carbon-rich feed streams and photosynthesis.
• Development of bioreactors to produce fuels from industrial and domestic wastes: Much of the current waste treatment consists of uselessly burning waste either by incineration or microbial oxidation. These methods, while easy, do not result in any significant energy recovery and are usually just another source of pollution. New bioreactor technology coupled with advances in the understanding of microbial populations will provide new sustainable waste-driven energy sources.
Microbes have been on this earth longer than humans. In fact, the ecosystem of this planet was made habitable for humans by the action of microbes hundreds of millions of years ago. Humans cannot exist without microbes. Consider that the human body is not even a single being but really a host-microbe community. The human body is host to about 1012 to 1014 microbes. Consider this relative to the 1013 or so human cells in the body. By this count we are about half human!
In a sense, the human body is just a bioreactor, which lives on another bioreactor—the earth. So, the future of the bioreactor is really our future.
With this said, the embodiment of the bioreactor in the future will be what we need it to be: a device to grow cells, make replacement organs, produce medicines, grow food, treat wastes, generate energy. The bioreactor of the future will have many manifestations depending on our needs and our imagination. Like any other tool, it serves a purpose and must change with that purpose.
As Abraham Maslow said, “When the only tool you have is a hammer, every problem looks like nail.” The bioreactor of the future may look like the bioreactor of today or may not. That is not the point. The issue is what the bioreactor of the future will do for us and how it will change our lives. For that we must understand what we need to build to solve our problems and not be limited by the familiar and traditional.
For inspiration perhaps a final quotation from Star Trek, “To boldly go where no one has gone before.” This should be our quest.
Vijay Singh, Ph.D., is general manager, GE Healthcare—Wave Products Group. E-mail: [email protected]