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From 2010.igem.org

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Table of Contents

• Introduction
  
• Ethical and Philosophical aspects of the implementation of Hydrocoli
  
• Bio-safety, bio-security and synthetic biology
  
• Issues of intellectual property rights
  
• A few words of caution for engineers: the difficulties of marketing the products of biotechnology
  
  • Some useful lessons from consumer attitudes towards genetically modified foods
    
  • The European view
    
  • The US view..
    
  • Recognizing information asymmetry in bioengineering as a driver of attitudes
    
  • Dealing with information asymmetries
    
  • Consumer rights: a look at agency
    
  • Labelling goods to reduce aversion
    
  • Technophobia.
    
  • Innovation, the “industrial religion“
    
  • Why innovations fail
    
  • Is saving the environment the way to consumers’ hearts?.
    
  • Conclusions.
    
• Economic and investment opportunities of Hydrocoli
  
• Conclusions.
  
• Bibliography.
  
  • Concerning Ethics and legislative issues
    
  • Concerning economics and marketing

 

 

Introduction

 

The object of this paper is not to add to the scientific contributions of our colleagues, but to provide an accessible overview of the type of question that the IGEM competition raises, all the while focusing specifically on the issues surrounding the ULB team’s project. We believe that if synthetic biology is to become a part of our daily lives, it is necessary to expand research to questions which are raised by this field but cannot be answered within this field. In this way we hope new perspectives can be explored outside of the usual and often restrictive frame of reference of “hard” science.
The hydrocoli strain that the ULB Brussels team has been working on for IGEM is designed to produce energy from waste. Specifically, the research concerns the production of hydrogen (in exploitable quantities) from wastewater. If the project is successful, Jules Verne’s “Coal of the future” may well be water, not as a composite body, but as the vehicle of the components from which hydrogen can be harvested.
This project has far reaching implications.  The fact that it focuses on the treatment of wastewaters and the production of clean energy means that it has potential repercussions which go above and beyond the scientific merit of the challenge. This is why a more pluridisciplinary approach seemed necessary.
This paper, which will examine the non-scientific issues surrounding the project, is made up of five parts. We begin with an examination of the ethical and philosophical questions raised by hydrocoli. This first chapter includes a brief explanation of the project in laymen’s terms: as it was written by philosophy and economics students, we wanted it to be accessible to our peers. Moreover, it is important to render the content of this type of competition accessible to anyone who is interested, particularly as biotechnologies concern everyone. The chapter on ethics also includes a cursory overview of the possibilities for humanitarian aid. This is developed more in depth in the fifth chapter, which is concerned with the possible economic consequences of its implementation. Chapter 2 concerns a pragmatic aspect of ethics, bio-safety, and includes a brief overview of the relevant legislation. Chapter 3 examines issues of property rights. Property rights, as a field which concerns both ethics and economics, makes an ideal segue into chapter 4, which examines the marketing of hydrocoli and of the products of biotechnology in general. The last chapter, as we mentioned, explores the economic possibilities of the implementation of hydrocoli.
For the purposes of this paper, we consider all the potential ramifications of the project, including those which may not be an issue in the immediate future. The importance of this approach needs no explanation in the wake if such ecological catastrophes as the hole in the ozone layer. As the saying has it, “better safe than sorry”. Besides the ethical reasons for this approach, the importance of taking into consideration every conceivable consequence, be it a question of an ethical, philosophical, economic, social or ecological nature, cannot be overstated if we hope for a successful use of hydrocoli in the future. A complete analysis of the project is thus a useful tool for our team if we hope to see our research applied one day.

 

Ethical and Philosophical aspects of the implementation of
Hydrocoli

 

" Oui, mes amis, je crois que l'eau sera employée un jour comme combustible, que l'hydrogène et l'oxygène qui la composent, utilisés ensemble ou séparément, fourniront une source inépuisable de chaleur et de lumière, et d'une intensité que la houille ne saurait avoir. Ainsi donc, rien à craindre... L'eau est le charbon de l'avenir.” Jules Verne, L’île mystérieuse, 1873.

This first chapter explores some of the ethical and philosophical aspects of hydrocoli. It begins with a popularized explanation of the project, aimed at the reader with no scientific background. We will then go on to explore the possible applications in terms of humanitarian aid and energy production. Lastly, we will take a more purely philosophical approach, exploring the implications of biotechnologies for Man’s place in the world through a heuristic approach.               
In order for the reader to understand the full implications of certain technicalities, it is essential to introduce a minimum of scientific lingo. Three of the technical aspects of the project bear mentioning for the purposes of this paper:

• The use of Escherichia coli[1]as the bacterial base.
• The fact that this new strain of E coli will aim at providing a complete water treatment process, through the inclusion of several modules, such as cellular death or heavy metal detection. 
• The association of wastewater treatment with hydrogen[2] production.

These three aspects are important for several reasons:
Firstly, because the use of E. coli as a base makes our modified strain easy to use and to improve upon: E. coli is the best-known and most commonly used bacterium in laboratory research.

 

Secondly, developing and exploiting this bacterium is not costly in terms of time or money because the technology needed is not particularly sophisticated. This is an important advantage for hydrocoli when compared with other water treatment processes.
Thirdly, the fact that, through synthetic biology, E. coli can be modified to include new characteristics is a non-negligible advantage. This makes it possible to transform E. coli into a strain capable of breaking down and neutralizing most matters commonly found in wastewater.
Your run-of-the-mill strain of E. coli can break down certain matters that are commonly found in waste. However, the modified strain will be able to break down organic matters such as cellulose, signify the presence of heavy metals[3] (perhaps even denitrify its environment[4]) and even eliminate methanogeneous bacteria which would otherwise curb the production of hydrogen by consuming said hydrogen through fermentation.  Having said this, if we are to follow the precautionary principle[5], it is safer to repress the methanogenous bacteria than to destroy them. In this case, following the precautionary principle means preserving biodiversity in the environment surrounding the water treatment facility. In fact, certain bacteria which we could inadvertently destroy could be essential components of the eco-system at the exit of the water treatment facility. 

If we were to opt for the elimination of the methanogenous bacteria, 10% of the water would have to be left in its natural state in order to preserve the biodiversity of the water source at the exit of the utility. Either way, precautions must be taken to preserve biodiversity because, as well as being an essential ethical principle, the preservation of biodiversity is a legal imperative.
The destruction of the E. coli strain after it has completed its tasks can be integrated as an automatic fail-safe into the bacterium itself, increasing its practicality and avoiding contamination risks. The risk of polluting the outside environment and modifying the eco-system are thus practically non-existent thanks to the poison-antidote system which the engineers are attempting to put into place in the cellular-death module.
The modification of E. coli in such a way as to give it the ability to fulfill several functions presents real advantages when compared to traditional water purification methods. Traditional methods require several different bacteria that must be monitored in a purification station. This is clearly a more complex, and therefore more costly, method.
Lastly, this strain is also modified in such a way as to produce hydrogen while fulfilling its other tasks. The production of hydrogen will be integrated into the water treatment system and it would be produced using the elements broken down from the waste present in the water. Moreover, synthetic biology actually makes it possible to increase the strain’s production capacity (by deactivation and over expression of certain genes) making it a possible cost-effective alternative to current energy generation methods. At this point, the team lacks sufficient information concerning energy production rates but it is very likely that the energy produced will at least be sufficient to run the treatment facility. Moreover, it is a very real possibility that the amount of hydrogen produced would exceed the amount necessary for a self-sustaining utility. The excess hydrogen could then be stored in sufficient quantities for domestic and/or industrial use. Furthermore, it should not be forgotten that even if the hydrogen production rates are small at first, our strain is a prototype that can be improved upon in the future. In any case, this project signifies real progress on an ecological and environmental front. No matter what the levels of hydrogen produced, any gain of energy in the process of waste treatment is in fact progress.
Hydrogen is non-polluting and its combustion emits only steam but this does not mean that hydrogen production techniques are environmentally sound. For an energy source to be truly clean, the production process itself must be clean. The most promising technologies are those which do not create any carbon monoxide or carbon dioxide because greenhouse gases are currently our most pressing concern. Our outlined method thus presents a serious advantage when compared to other methods because it creates no greenhouse gases at any point.
Hydrocoli is even more advantageous than most energy sources that fall under the heading “renewable”. For example, the production of electricity through photovoltaic panels or windmills is less advantageous, qualitatively speaking, because the infrastructure relies on polluting or exhaustible resources, such as terbium, dysprosium and neodymium which are ‘rare earths’[6]. When you add the fact that the maximum period of exploitation of these technologies is not sufficiently long to justify their energy costs, it is clear that they are not energy solutions for the long term. The aforementioned problems are non existent with technologies which rely on synthetic biology because it uses living elements, bacteria, which produce absolutely no waste and are exploitable in existing infrastructures.
Besides the advantages for energy production, hydrocoli could have positive consequences for water access: new filtering and purification facilities that run with technologies relying on synthetic biology could revolutionize humanitarian aid and development. Running water is so common in industrialized nations as to be taken frequently for granted, but in developing countries water is an extremely problematic issue, so much so that the United Nations made “the decrease by half of the percentage of the population without access to drinking water[7] or basic cleaning facilities” one of their urgent “goals for the Millennium[8]” to be reached by 2015. Furthermore, the issue of access to drinking water goes hand in hand with the issue of the purification of wastewater.  In fact, contaminated water is responsible for the deaths of 5000 children per day (one death every twenty seconds) and ingested wastewater can cause diarrhea, making it is the main cause of mortality in children under five.
            The ubiquitous and difficult nature of the wastewater treatment problem arises from its complexity. The fixed costs of water purification are huge, meaning developing areas do not have access to the kind of global water treatment means that are commonplace in the west. This is why the development of our simple water treatment technology could have a revolutionary effect on humanitarian aid.
Indeed, the infrastructure needed is minimal, making this technology potentially cost-effective and easy to use for groups on a small scale, such as families. Water purity is a problem especially in warm weather areas, because that is where bacteria survive and breed. Our innovation in fact takes advantage of this fact, because the modified strain of E. coli is well-suited to just such areas.

Rare earths These are chemical metallic elements extracted from minerals. This category includes scandium, yttrium and 15 lanthanides. The elements have particular properties and are highly coveted in the alternative energy development field. Terbium, dysprosium and neodymium are lanthanides used in hybrid cars, in wind turbine generators and in solar technology. Their demand is constantly growing. This poses a serious problem. It is estimated that terbium 65 stocks will be depleted in 2012. Moreover, mines where they are extracted are often extremely polluting.

Another major water contamination problem arises due to the absence of toilets. Once our technology is implemented, wastewater could be evacuated and treated on the spot even in the most isolated areas.
The difficulty of access to clean water is an important factor for economic development because the difficult task of finding water takes several hours a day. Generally the task falls to women and children, who may miss several hours of school fulfilling the chore.
Access to clean water is also absolutely essential in the fight against many diseases which can be simply eradicated if adequate wastewater facilities are provided. Currently, water purification tablets or filters are distributed by several NGO’s but these methods don’t have the added economic and social value of the implementation of a water utility and an integrated distribution circuit and are not a long term solution because reliance on foreign aid creates new problems.
The ideal end result of our team’s project would be the easy installation of a water network, on any scale (village, city, country) through the implementation of small purification centers. The water purification would be linked to the production of electricity from hydrogen for areas that are cut off from the main energy networks. In this way and on a local scale, these utilities could provide clean water and energy from a self-sustaining source.
The possibilities for developing countries are the driving force behind this idea, but this technology is also potentially very advantageous for industrialized nations. We have already mentioned the advantages of this technology when compared to traditional methods. In addition to those characteristics which were already mentioned, E. coli has the added particularity of treating nitrates and heavy metals which are more particular to industrial nations.  Due to the vast quantities of wastewater in industrials lands, one can also imagine that water treatment would create a hydrogen surplus which could be used for industry.
For almost a century, petrol has dominated the energy sector and hence many industrial sectors, notably transport. Developing alternatives is difficult in the face of the petroleum monopoly, especially when it comes to classical methods of producing hydrogen which are not as cost-effective as fossil fuels.  However, synthetic biology gives us another way to produce hydrogen, but, unlike other ways, it is actually potentially competitive enough to make serious headway on the energy market. 
The IGEM competition may fulfill a valuable role in encouraging the development of alternatives to traditional methods which always involve a trade-off between financial costs and environmental costs. Could it be that with synthetic biology we could have our cake and eat it too?

Millenium goals The 189 members of the UN have set a series of objectives to be reached by 2015: Reducing extreme poverty and hunger. Ensuring primary school level education for all. Promoting sexual equality and the autonomy of woman.  Reducing child mortality rates. Tackling the health conditions for childbirth.  Tackling HIV, AIDS, and a series of other illnesses.  Promoting sustainable development. Putting into place a world-wide partnership for promoting development. These 8 objectives are specified in quantitative terms; for example, reducing unemployment or poverty by a specific percentage.

 

If we put aside ethical and ecological concerns for the moment, we can see that industry and other profit seeking activities can also be conquered by this technology (for further development, see chapter 4). All the concerned parties could continue to pursue their selfish interests without doing damage to each other. This could lead to the deconstruction of the traditional polarization of industry and ecology, at least where energetic resources are concerned. If we were to philosophically deconstruct these opposed poles, developing this alternative could even reduce the traditional gulf between the corporate world’s interests and philanthropic interests.
It must be said though that the ideas developed here are not meant to be normative. We are fully aware of the dangers of idealism, and mentioning all the possibilities of this technology is merely a way to underline its potential power. Moreover, the mention of this deconstruction of the polar opposition is pure speculation and aims at highlighting the latent strength of the concept of a society governed by the production of clean hydrogen. In practice, this kind of social revolution is not likely and could even lead to concerns about utopianism. If positive change is possible, it will come about little by little, taking the form of a trend rather than a complete discontinuity. Indeed, sudden and extreme social change is usually best avoided.
As we have seen, the ethical issues are numerous. Philosophically, there is also much to be said. In fact, if this technology were to be rendered functional, it could change the position of the human subject in his environment. Currently, when it comes to ecological concerns, the traditional distinction between Nature (and its flora and fauna) and Man is as follows: Nature, as opposed to Man, produces no waste; everything changes but nothing is lost. Nature is a delicately balanced system which is constantly recycled and renewed. Philosophically, Man can be seen as the element which breaks nature’s cycle, disturbing the system. This rupture with his environment is one of Man’s essential characteristics and can be linked to a self-consciousness which is constructed in opposition to what is outside of the self.
The awareness of being an element in the environment is a fundamental difference between Man and plants and animals. Plants and animals can be seen as one with their environment, the essential building blocks that make up Nature. Animals live in an ecosystem to which they are indebted. They live in the ecosystem, but are also a part of the ecosystem, as essential to its make up as trees to that of a forest. In contrast, Man does not pay tribute to a specific ecosystem; he does not even live in an ecosystem, in the strictest sense of the word. An ecosystem is defined as follows: “the association of a community of living species (biocenos) and a physical environment (biotope) in constant interaction with each other”[9].  Man has managed to adapt to almost every type of weather and geographic conditions. However, even if not indebted to a specific environment, Man, as an inhabitant of planet Earth, depends on the environment, taken as a whole.
Nature can be compared to a huge perequation in which all the elements are constantly adjusting to maintain equilibrium. In this metaphor, Man is the unknown quantity which disturbs the equilibrium. The fact that Man produces waste is the crucial issue here. The idea of waste itself is entirely anthropocentric, as made up of artificial or artifactual and thus non-natural objects. Generally, waste refers to everything that nature can not break down and recycle in order to achieve its all important equilibrium. The vast majority of these elements are byproducts of Man’s activities.
If we were to push our team’s project to its logical conclusion, we would witness a new paradigm for the conceptual place Man can occupy in Nature. In fact, the almost complete treatment of waste present in used water is used here to produce energy directly, reproducing the kind of self-sustaining cycle found in nature.  Through the decrease of the direct exploitation of natural resources and of the quantity of waste, Man can minimize the disequilibrium that he creates in the system.   To go back to our comparison, Man could then create a new equilibrium in which he plays a part comparable to that of other species. He would then tend towards the equilibrium of a new system on an individual scale, rather than throwing the entire global system out of order, and what is a system at rest but the sum of its sub-systems which are all at rest? To return to our metaphor, we can now say that Man could reach the optimal equilibrium in his own system, contributing to maintaining, and not destroying, the natural system which is an extremely complex equation.
From this point, we can go on to a more heuristic philosophical development. If we accept the conclusions of the previous paragraph, their counterfactual is also true, implying that the disturbance of each sub-system can disturb the system, in this case, Nature, as a whole. This somewhat basic and obvious axiom makes it possible to develop a prospective reflection based on a fear heuristic[10]. What this means is projecting ourselves into a future, more or less distant, by imagining the various consequences that may arise from the current situation. To a certain extent, this method is commonly used, notably in climate studies. The real philosophical interest here however lies in the interpretation of the results from an extra-scientific point of view.  Basically, this consists in taking into consideration the results of our thought experiment from a human standpoint and not merely from the Cartesian standpoint. This method can be seen as a sort of philosophical modelization.
If we imagine the future and the result is fear or anxiety, the future we are headed for must be contrary to the aspirations of humanity. This is true because fear has proven to be the most efficient tool when it comes to avoiding the pitfalls of utopianism and hubris. If we take the current parameters of resource exploitation and the resulting pollution and interpret them, from a purely scientific point of view, to imagine the coming century, what we have may be sustainable for the human race but instills fear in our hearts. While we may manage to survive in a world where the air is compromised, the weather thrown out of whack and the majority of animal and vegetable species destroyed, the picture this paints is met with horror.
This alone is a sufficient reason to make an effort to escape the terrible inertia which pulls us closer and closer to the center of the ecological black hole, to the point of no return. Patching up the wooden leg that we are currently standing on will not help us; our inertia must be reversed as soon as possible. Despite this urgency, the current trend is to follow an ostrich policy, as evidenced by the continued massive exploitation of non-renewable fossil fuels, the use of which is already compromised itself and may soon compromise our very existence. 
While it may seem that we have gotten off track, we believe that IGEM and our project specifically are directly linked to the energy and environmental issue, as they offer alternatives which are infinitely more advantageous than what is currently on the table. The beginnings of this project which concerns waste and hydrogen are a wonderful way to address, and perhaps even resolve, two of the major problems of the 21st century: the energy crisis and the intimately linked need to reduce pollution. By encouraging research in this area through the development of our prototype we hope to reconcile these two staggeringly huge challenges and solve them together.

 

Bio-safety, bio-security and synthetic biology

 

Besides the ethical analysis that any genetic modification project demands for deontological reasons, the IGEM competition requires that we take the ethics of synthetic biology into account on a more formal level through the analysis of bio-safety and bio-security. 
Bio-security is an issue which stems directly from bioethics. It refers to a series of established procedures designed to avoid the sanitary problems that can arise from synthetic biology and that are called into play by ethical concerns. Bio-security gives us the legal framework which is necessary to preserve the environment and public health in the face of the possibility of misuse.
Legally speaking, bio-security refers only to genetic engineering involving genetically modified organisms or pathogenetic organisms. In Belgium, bio-security regulation falls under the heading of work environment safety but bio-security and bio-safety standards vary from country to country. There are however some which are enforced on a European level or internationally.
In practice, bio-regulation is enforced by the prevention council and the bio-security head. The law requires that every laboratory where genetic modification or the use of pathogenetic organisms take place must appoint people to fill the two aforementioned positions. The legislation also requires the existence of a local bio-security committee whose job is to deal with the daily problems faced by the relevant institutions.  Belgian law doesn’t contain specific requirements concerning the composition of these committees, but they are generally made up of professionals who work in the field.

First thing, all laboratories must obtain an environment license, delivered by the competent regional authorities, before they can begin operations. The authorization is delivered after appraisal by the Bio-security and Bio-technology Service, a federal body. As an example of the concepts and instruments relevant to bio-safety we will now discuss the procedure that a lab must follow in Belgium.
Firstly, any installation where a confined activity involving micro-organisms or dangerous or modified organisms takes place must register with the competent regional authority. According to the installation and the level of risk of the activity, the business may need written authorization. Moreover, a legal decree stipulates that any request for an environmental license must include a risk evaluation of the research to be conducted. The SBB then plays the role of technical expert and expresses an opinion on the risk evaluation. The SBB report must be given in with the licensing request. The file containing all the relevant information for a notification of confined use constitutes the bio-security report.
In order to make the information and authorization procedures easier and to reduce the amount of paperwork, the SBB has come up with notification forms and a user’s guide. These are based on the relevant legislation but also on field experience in applying the laws.
Before beginning a new research project, the researchers must complete a detailed description of the project and its goals. Their description is then the object of a risk evaluation. The level of risk is measured on a scale going from 1 to 4. This risk estimate is based on the type of organism used (inoffensive bacteria, animal, virus, etc) and on the goals that the research is aiming for. The risk evaluation aims at identifying risks intrinsic to the activity but also the possible consequences for Man, for flora and fauna or for the environment generally speaking (for example, when using bacteria which are essential to biodiversity or in preserving topology).

The protection of the environment has its own enforcers, the environmental inspection agency, which is responsible for checking licenses and authorizations: the inspectors are authorized to seal a laboratory if it has been found guilty of illegal research.  Refusing to respect the sealing order can lead to punishment and even to imprisonment of the guilty party. Belgian bio-security and safety legislation was reviewed in 2002, as was the legislation concerning environmental licensing.
In addition to the regulation concerning laboratory research, the development of genetically engineered organisms for industrial use requires a specific authorization process. Specific emergency and intervention measures have been established for genetically modified micro-organisms. These procedures can be implemented quickly thanks to the information contained in the forms that the researchers must fill out before beginning activities. This information is in fact crucial in case of emergency and includes such essential points as the type of organisms being modified, the safety measures of the lab, quantity, etc.
The policies we have listed are largely applications of European Union directives. EU directives are mainly established to avoid one country having to suffer the consequences of a neighboring country’s activities, for example in the case of contamination through the exchange of goods. A number of international treaties have also been put into place, along with the mutual control needed to ensure that they are respected. This type of regulation is necessary if these treaties are to be respected, and their enforcement is in everyone’s interest, as bacteriological contamination, once started, is virtually impossible to control. The relevant legislation on an international level is contained in the “Cartagena Protocol”.
This protocol was ratified by the UN in 2000 and has been active since 2003. It aims at avoiding biotechnological risks and at gathering the data concerning these risks on an international level thanks to an information exchange center. This center encourages transparency and accessibility of information, allowing for example for a healthier and more efficient management of commercial activity in developing countries.
The Cartagena protocol demands respect of the precautionary and prevention principles in the absence of scientific certainties in order to limit the risk. This is an understandable precaution because these risks, in certain cases, as in the development of GMOs for industrial use, could have repercussions that resonate on a national scale or beyond.    To put it another way, French law puts it as follows: “the absence of certitude, given a specific state of scientific and technical knowledge, should not slow down the implementation of effective and appropriate measures which aim at avoiding serious and irreversible damage for the environment at a reasonable cost”.
The precautionary principle entered into the legislation in 1992. It is not merely a philosophical concept, but a normative imperative. Let us add that legally no one is authorized to manipulate organisms for pathogenetic goals, not even defense forces. Bacteriological weaponry is thus an area of research which is theoretically forbidden by law.
Bio-security and bio-safety norms include, beyond the legal aspects, a series of more technical directives aimed at the scientists who conduct laboratory research. These directives are the practical applications of the federal law on a more concrete level. They are mainly concerned with the management of biological decontamination. Biological decontamination involves treating air through the use of specific filters, treating liquid which may contain biocide solutions or detergents, the treatment of solids which must be incinerated and the treatment of elements which may be radioactive.
Despite these measures, zero risk situations do not exist. This is one of the reasons why it is so all important to evaluate and compute the risks. The precautionary principle is always meant to be applied in the field of biotechnology because the technicians are working with organisms which are often invisible to the naked eye and which can be dangerous because of their instability.
The bio-safety manual and the waste elimination manual are two deontological guides which include the legal imperatives to be respected when conducting research.  They are not included in interior law but are necessary for the correct application of the directives in a specific institution.
This concise section on bio-safety and security is meant to be a short guided tour of the different practices in use. The extent of the measures concerned shows us to what extent biotechnologies are supervised. The most important point is to ensure that bio-safety is not taken lightly because inadequate risk management could lead to a catastrophe the likes of which we’ve never seen. It remains true that synthetic biology has much to offer us but in order to ensure that it does not become a poisoned chalice, it is important to be careful. Norms and a surveillance and peer-review principle are essential tools in avoiding the misuse of science. The risk of instrumentalization is particularly present in the case of synthetic biology because this is a relatively young field. This means it remains obscure for many but is ever more ubiquitous. Bio-safety and bio-security regulations are absolutely necessary if we are to avoid, inasmuch as possible, scenarios in which a sorcerer’s apprentice or mad scientist would have the ability to create a diabolical alchemy involving the worst poisons and most ravaging plagues.