Biotechnology today and tomorrow What will historians record as they look back to the second half of the twentieth century and to the efforts of biotechnology to secure for itself a significant place in the large-scale chemical industry? Will the record show that we were slow to grasp opportunities or will it accuse us of attempting to bring a complex tech- nology to birth before the biosciences were sufficiently advanced? Perhaps the verdict will be that we were about right in our efforts, but that abrupt economic and political changes seriously hindered development. Per- haps we will be seen to have weathered all the storms and succeeded.

It is pertinent now, therefore, before history is written, to consider whether we should assume that biotechnology has a part to play in large-scale produc- tion processes.

The chemical industry is in business to make pure products with minimum by-product worries. How does this relate to the world of biology, where a multiplicity of products are made depending on a microorganism's internal needs and response to its environment? To nature these other products are not wasteful but part of the overall complex balance of life. Out of this context, however, they may be discounted by industry as waste, in terms of both the undesira- bility of production and problems of separation and disposal.

Ought we then to limit our horizons to only those end products for which a suitable chemical or natural route does not exist at present and, in our judgement, is unlikely to exist in the near future? Is it sensible to extend this outlook to include beneficial use of organic waste streams on a local basis, or may we presume on the advancement of scientific knowledge to enable us to succeed 'on the day' with much wider possibilities?

Questions of timeliness and pre- paredness are extremely important to industry when considering its atti tude to biotechnology, particularly in view of the resources needed, the time required for development and the generation of business confidence that are involved in starting large new competitive processes. Industry must decide, on the basis of fact and specu- lation, whether or not the time is ripe for a significant investment in this area and to what extent projects which are possible can be made probable and

then actual by the devotion of develop- ment effort.

Part of the answer lies in further examination of the security of supply of a wide spectrum of natural products and of whether industrially derived alternatives are acceptable. Part of the answer also lies in the security of supply of non-renewable resources, their pricing relative to renewable ones on a world-wide commodity basis, and the consequences of future changes to less directly usable forms of non-renewable materials.

A further part of the answer may be deduced as we move from physical, through chemical, to biological systems and find ourselves less able to employ general correlations and in need of more fundamental knowledge. For example, whatever the profound physical explanation underlying the phenomenon of gravity the chemical industry does not need to know it in order to make everyday use of it. Chemical engineering serves us well enough when it is able to describe complex physico-chemical processes in simpler, usable forms. But it frankly acknowledges a lack of fundamental understanding by providing limited range correlations having experi- mentally determined coefficients and power indices for factors suspected of contributing to the underlying complexity. In inorganic catalysis, we begin to see the benefit of having a good understanding of the exactness involved if we are to be able to design new catalyst systems.

• Drugs Increosing

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Scale of production Figure 1 Impact of biotechnology with time

When we come to the industrial use of living microorganisms, however, we wish to influence the micro- organisms for our own ends in such a major way that we must more fully understand how and why they prefer to do certain things and not others if we are to constrain their performance to match our criteria of efficiency. Such complexity of understanding requires well managed interdisciplinary effort if the biosciences are to provide the necessary undergirding for indus- trial ventures.

Biotechnology vs. time

A simplified view of biotechnology vs. time, partly historical and partly speculative, is shown in Figure 1.

Biotechnology up to and including the 1970s provided economic routes to complex molecules, such as drugs and enzymes, which are difficult to synthesize chemically. Outputs are relatively small but result in benefits out of all proportion to scale of production.

By the 1980s technology has developed to the point where large- scale production of simpler products such as single cell protein (SCP) becomes economically feasible.

Further development takes us into the 1990s and beyond, and opens up the possibility of making simple organic molecules economically. In other words, we are beginning to compete with well developed chemical routes to a range of products. To what extent actual biosynthesis, as distinct from biocatalysis, is involved in this remains to be seen.

Biotechnology

1970s [

1980s

1990s

0141 --0229/80/040327--03 $02.00 © 1980 IPC Business Press Enzyme Microb. Technol., 1980, Vol. 2, October 327

Industrial views

J Fermentation I ~ Dewatering I I

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Figure 2 Major plant areas of biochemical processes

Today's pos i t ion

Before we get too far with speculation about the future it is necessary to take stock of the position today in order to assess its strengths and weaknesses and to point out areas of ignorance which must receive attention from those committed to the application of bio- science and technology. Figure 2 shows four basic areas of biochemical produc- tion process: fermentation, dewatering, drying and extraction/purification.

In which of these areas does most fundamental knowledge lie? A glance at readily available wall charts of metabolic pathways or at the agenda of most biotechnnology conferences provides the answer. It is fermentation.

Why is this so? Industrially this is a hangover from the past where, tradi- tionally, products have been in the high value category. There has been little incentive for overall process optimization because selling prices have been related to high risk research and to marketing requirements rather than to actual production costs. Because of this, academic research effort and undergraduate training have also very largely been directed at fermentation. Proper optimization is in any case an interdisciplinary exercise and academic institutions are not normally expert at such activity because of specialization and lack of practical engineering guidance. Perhaps the finger points most sternly at chemical engineering inputs to biD- technology because in this area, the vital importance of overall process costs for lower-value larger-scale throughput products should be under- stood. Sadly, the usual experience is to find fermenter KLa measurements being made and reported endlessly. The last 5% of ultimate aeration performance seems to prevent observa- tion of the yawning chasm of ignorance beyond the fermenter.

There is a desperate need to explore the less well-trodden and, at present, less glamorous world outside the aeration stage. Those who tackle challenges in the separation areas will enable progress to be made and, dreams to become reality.

S o m e ways forward Most processes in the chemical industry move along a learning curve. This is

Drying

i b 1

Extraction t - - and

pu r i f i co t ion

necessary to keep the product market- able. Increase in stream size and reduc- tions in invested capital and operating costs per unit of product are all involved. An illustration of this, in terms of operating cost, is provided in Figure 3 for ammonia and methanol plants. Learning is expressed as the ratio of actual energy usage to theoreti- cal minimum. It is evident that the ratio has been roughly halved over a period of 20 years. We may expect bioprocesses to do something similar and perhaps faster if the incentive exists.

Three possibilities are outlined here as a means of moving towards the economic biotechnology of tomorrow.

Refinery concept One possible way forward is to

accept the fact that microorganisms produce more than one product and approach this positively by devising a biochemical refinery. Figure 4 shows a typical petrochemical operation

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Year

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Figure 3 Learning curve for ammonia and methanol

Basic products

Gas

Crude

oil

based on the carbon source of an oil well. Crude oil is refined into products and this adds to its value. Separation, however, does not add as much value as further reaction/separation stages and smaller quantities of higher value products can be made by further reaction.

Figure 5 shows a speculative parallel where the fermenter replaces the oil well as the source of basic products. The refinery then splits open the microorganism and extracts a variety of products. What these products are likely to be and what reaction con- stituents will be involved, is unsure since in 1945 it would also not have been possible to make accurate predic- tions about the product range of a present day petrochemical complex.

Biocatalysts Immobilized enzymes, whether in

whole cell form or extracted and resupported, have been in use for some time to catalyse a number of liquid phase reactions. Today, in laboratories around the world, there are several enzyme systems under development for catalysis of a whole variety of petrochemical reactions. The use of selected microbial catalytic pathways is expected to lead to quite specific reactions and thus avoid unwanted byproducts which necessitate extra removal steps downstream of the reactor.

What if one or more of the reacting species, gas or liquid, is highly insoluble in the aqueous environment required by the biocatalyst? Present concepts of fixed bed catalyst and agitation requirements for mass transfer are not compatible. Can other concepts familiar to the chemical industry be employed such as gas phase or homogenous/dispersed heterogenous catalysis?

Advancing techniques of gene manipulation

A whole range of techniques for gene mobilization, transfer and dupli- Added value Exlra added value

products products

Fuels Ii Arornolics

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oil [ Olefins

Residues

0 CI N S

J~ / Derivatives

~'T Derivatives

T T T 0 CI N S

Source Separation Reaction/separation Reaction/separation Figure 4 Oil refinery and petrochemical operations

328 Enzyme Microb. Technol., 1980, Vol. 2, October

cation is covered under this heading. Mutation, which has been deliber-

ately and routinely practised for a long time, has now been supplemented by recombinant DNA work. This is still in its infancy but the limited amount of success so far is encouraging. Genetic engineering will, however, only realize its potential if biotechnology as an industry exerts a market pull for its services in setting targets and time- scales for achievement.

The prizes are large and there are signs that the target setting approach may already be reaping some benefits. It is possible then that the time scale for effective use of recombinant DNA technology may be shorter than is generally believed.

Guidance for the future

Tomorrow's world will not differ from today's in respect of a number of fundamental and economic features, so it is possible to offer some general guidance for the future, in addition to the few specific suggestions outlined for reaching it.

We have a problem in industry and, stated over simply, it is this. The academic world selects which frontiers of the biological sciences it will explore and which vehicles of exploration it will use. This is a perfectly legitimate expression of academic freedom. After several years the work has progressed from early ideas to the point where it is of sufficient interest to the research and development end of industry, and a few years of joint work might then take place to assess its potential. In the second decade, from the start of serious laboratory work to the setting up of the first large-scale plant, con- siderable time and effort is spent trying to squeeze potentially beneficial properties into the mould of economic reality. Sometimes this is not possible and backtracking is difficult because the detailed research has been specific rather than general. If development is successful we must then be assured of economic production over a further 20 year period.

Basic products

Basic raw materials

C 0 2 Bio crude

Fermenter I ! L_

Products in solution

Source

Figure 5 Bio-refinery possibilities

Biocatalyst ] preparation ]

Reactants

I I

J Reaction

I I I

Separation

Productivity Activity Concentration Nature Life

Temperature Mass transfer

Figure 6 Outl ine of biocatalysis process and key economic factors

Industrial views

l I Purification I

I Product ,,

Specificity O/emil conversion efficiency

With this four-decade timescate in mind, it is vital for the application of biotechnology that the academic world be aware of those factors which help or hinder such application. This is not an argument for applied research alone but, all other academic driving forces being equal, these factors should at least be considered at the conceptual stage of research. As an example, some of the important factors which will determine the economics of bio- catalysis are indicated in Figure 6, which outlines the overall process. Further guidance can be offered with regard to the relative overall complexity of chemical and biological routes to a particular product.

High temperatures and pressures are used in many chemical processes to drive the reaction in the required direc- tion and much of the heat of reaction is usefully recovered or efficiently supplied. It is inevitable though that industry's first look at living systems is one of envy since these systems accomplish their reactions at essentially room temperature and pressure. Apart from realizing that few useful heat sinks are available to recover heat from biological reactions, a second look might also include a few questions about what distinguishes a typical bio- logical system from a typical chemical one and the implications of those differences on the overall production process (fermentation and separation). One relevant answer is order.

Added value products

Extra added value products

-,,.pRe f ined protein o{ysaccharides

Nucleic acids

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\ - . ~ " Amino acids k "Antibiotics Aliphatic acids

Separation

rivotives

Reaction/separation

This order, however, is only achieved at a price. That price is paid by the processes employed for separation of reaction products. An aqueous stream containing 1% of highly ordered organic material may be regarded by the micro- biologist as concentrated, but by the chemical industry as only fit to be put to drain!

Timely and prepared?

Exciting possibilities abound in bio- technology and the rate of progress of knowledge is rapid. But, as I hope I have already shown, biotechnology must earn its place in the chemical industry.

Is the large-scale application of bio- technology timely and are we prepared for it? Where the answer to both these questions is 'yes', we will employ our industrial technology and manage- ment skills to hasten the implementa- tion of biotechnology in the large-scale chemical industry. Where the answer is 'yes' to the question if timeliness alone, we will encourage the exploration of the frontiers of bioscience in order to acquire the necessary fundamental knowledge. If we can only answer 'yes' to the question of scientific prepared- ness, we will continue with the deve- lopment of chemical technology while waiting for prevailing economic and political climates to change. And if the answer to both questions is 'no' , we will leave it to future generations to dream and work for large-scale fulfillment.

Acknowledgements

I am grateful to the Board of ICI Agricultural Division for permission to publish these personal views of bio- technology. My thanks are also due to many colleagues for stimulating discussions in this area and, in parti- cular, to Mr C. W. Gent, Dr E. H. Dunlop and Dr P. J. Senior for contri- butions to this paper.

D. A. Hines ICl Billingham. Cleveland, UK

Enzyme Microb. Technol., 1980, Vol. 2, October 329