Designing the Microbial Research Commons: Proceedings of an International Symposium (2011)

2. Microbiology in the 21st Century
– Joan W. Bennett²

Rutgers University

The Commons Defined

A Primer in Microbiology

In microbiology we are working at a scale that is orders of magnitude smaller than what most people are used to thinking about. Many of the microbes that are studied, like bacteria, are smaller than single cells of the human body. Thousands of Bacillus cells will fit on the tip of a pin. Most archaea and bacteria are about the size of the nucleus of a eukaryotic cell. Viruses are smaller still, so they are difficult to visualize unless one has an electron microscope. Because microbes are so small, early microbiologists figured out ways to grow them in the laboratory so we could see populations of them growing together in colonies. Microbiologists have had to be experimental. Many of common microbial techniques were developed by 19th century bacteriologists. While the symbol of the classical microbiologist is the microscope, the symbol of the experimental microbiologist is the Petri dish. Although we often think of a microbial colonies growing

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² Presentation slides available at http://sites.nationalacademies.org/xpedio/idcplg?IdcService=GET_FILE&dDocName=PGA_054556&RevisionSelectionMethod=Latest.

only on Petri dishes, that is a bit of a misconception. Nature frequently provides its own colonies. Sometimes you can see whole populations of microbes “bloom.” Purple sulfur bacteria create a rather pretty colony, for example. Those of you who are skiers have probably seen “water melon snow” created by cold-tolerant algae and cyanobacteria that grow on snow and ice during alpine and polar summers. And, of course, in the world of rot and ruin, microbes are frequently visible. They make ugly colonies when they spoil fruit, vegetables, and other food stuffs. Microbes also have been known by the good things they do, such as their uses in bread making and fermentation, which go back to the early stages of civilization. Yeast is the microbe used in making bread; it provides the leavening. Similarly, yeasts are essential for the fermentation of wine and beer. People harnessed yeast metabolism for centuries without knowing that they were working with a microbe.

Microbes are best known for the diseases they cause. Pathogen is the general name for an organism that causes a disease, and is used to describe all microbes able to cause disease in animals and/or plants. Infectious diseases are those that spread from one person to another. An infectious disease can be more formally defined as a clinically evident disease resulting from the presence of pathogenic microbial agents, including viruses, bacteria, fungi, protozoa, multicellular parasites, and the aberrant proteins known as prions.

When we consider microbiology, we often think about the traditional scourges. One is leprosy, which has many references in the Bible and other classical literature. The causative bacterium of leprosy, also known as Hansen’s disease, is Mycobacterium leprae. A second notorious infectious disease of antiquity is plague caused by Yersinia pestis. The “Black Death,” as it was known, killed a third of Europe’s population during the 14th century. It got this name from the black skin splotches it caused on affected people. Swollen lymph glands, or buboes, are the basis of the name “bubonic plague.” The word plague, which should be used narrowly to describe just that one disease, often has come to be used as a general term for any devastating epidemic disease. Tuberculosis, for example, is sometime called the white plague.

In addition, many viral diseases have been known since ancient times. These include chicken pox, influenza, mumps, polio, rabies, and yellow fever. Most of these diseases are still very much with us. On the other hand, smallpox, in one of the great triumphs of public health and microbiology, has been eradicated. Young people are no longer vaccinated. A corollary of the eradication of small pox: If you want a good bioterrorism weapon, you do not have to do any genetic engineering—just unleash smallpox again.

Professional Societies, Journals, and Culture Collections

What about the professional societies organized by microbiologists? Microbiologists started organizing themselves into professional groups right after the research of Koch and Pasteur changed the face of medicine and public health. The American Society for Microbiology (ASM), the society that I know best, is not only the world’s oldest microbiological society but is also one of the world’s oldest biological societies. It was founded in 1899, well over a hundred years ago. It was initially named the Society for American Bacteriologists, and for quite a while, even though it had members who worked on viruses and fungi, its members referred to what they did as bacteriology. The Society name was changed from the American Society for

Bacteriology to the American Society for Microbiology in 1961. The ASM now has over 30,000 members representing more than two dozen disciplines of microbiological specialization plus a division for microbiology educators. It is international in scope, with about a third of the members being from outside the United States. For much of its history, the ASM has published a number of journals. The Journal of Bacteriology was the first one. Now several additional premier journals that specialize in different facets of microbiology are also published by ASM such as Applied and Environmental Microbiology, Eukaryotic Cell, Journal of Clinical Microbiology, and Journal of Virology. The Society also publishes a monthly magazine called Microbe, formerly ASM News, as well as an education journal.

Early in its history, ASM was deeply involved in the publication of Bergey’s Manual, which has been the premier reference book for compiling the names of microbial strains. The first edition was initiated by action of the Society of American Bacteriologists by the appointment of an Editorial Board chaired by David H. Bergey. The first edition was published in 1923, the second edition in 1925, and a third edition came out in 1930. Bergey’s Manual is now owned and produced by an independent trust.

Genomics and the Microbial Commons

The landmark microbiology-biotechnology patent case was Diamond v. Chakrabarty, decided by the U.S. Supreme Court in 1980. Diamond was the Commissioner of the U.S. Patent Office and Chakrabarty at the time was employed by an oil company. The subject of the patent case was not a genetically engineered organism, but rather was an organism that was claimed to chew up oil waste. In a close decision, Chakrabarty’s side won, and the ruling established the precedent that microbial and other life forms could be patented. By the time this case came along, I was a young, recently tenured associate professor and I remember how excited I felt by the sense that we were entering a new world for biotechnology. Significant scientific and commercial advances have kept coming since that time.

The pace of DNA sequencing then got faster and faster, and the whole field of genomics was born. Genome is an old word used in genetics—cytogenetics actually—to describe the entire genetic content of an organism. Genomics was adopted in the late 1980s to describe the new sub-discipline. It is a word used many ways, but we would not have genomics without the tools developed by the study of bacterial genetics. The components underlying the ability to sequence DNA were first developed in microbiology. For example, much of the sequencing for the human genome project was done using the M-13 bacteriophage.

The Microbial Commons in the 21^st century

The published scientific literature raises other questions. We have a long-entrenched tradition that many professional societies exist almost solely to publish their journals, and that these societies get much of their revenue from protecting and selling those publications. The advent of digital publishing has shifted the economics of scientific publishing. It takes a great deal of time for scientists to engage in peer review. Someone has to edit and organize the efforts into a coherent publication. If scientific societies do not do so, who will?

Thus, the tradition of peer reviewed scientific publications of research findings is not going to go away. It is scientists who keep the publication system going, with their long hours in the laboratory doing experiments followed by long hours devoted gratis to editing and reviewing. Every scientist worth his or her salt devotes a lot of time—free, unpaid time—to peer review, and not just to publications, but to grant proposals as well.

About 50 years ago, an increasing number of commercial units started publishing scientific journals. These professional journals have become increasingly expensive to obtain. I could not find a study on the price of microbiology journals, but there are several good studies on the cost of chemistry journals. According to the Library Journal Periodicals Price Survey, the average cost of a chemistry periodical to a library in 2009 was over $3,700. If you multiply that by the number of journals a research library is supposed to carry, the costs are crushing.

Another development comes from government. In response to congressional legislation, the National Institutes of Health now requires grantees to put their research articles online, free of charge, within 12 months if they have been supported by NIH funding. This has been a good development for more open availability of research results but the full implications for the long term sustainability of the current scientific publication system remain unclear.

In contrast to the world of the traditional scientific paper, the situation with databases is more favorable to open communication. As part of the genomics revolution, the databases are relatively new, with much of their development having happened during the past 20 years. Since its beginning, genomics has generated a number of other “omics”—proteomics, metabolomics, and so on—and there has been a convergence of the bioinformatics community with the experimental microbiology community.

Bioinformatics brings mathematical, statistical and computing methods to the analysis of the vast amount of DNA sequence information, gene expression data, and other information generated from the new biological disciplines. These are huge datasets. These databases facilitate studies by a new kind of biologist who does “in silico” research.

The pace of discovery has speeded up incredibly since the early years of recombinant DNA research and gene sequencing. In the beginning, we had to work hard to analyze a few thousand DNA base pairs. Today, however, the speed is absolutely incredible. The sequencing technologies that are used at the big sequencing centers now are generating vast quantities of DNA sequence data at a rate that is hard to imagine. Moreover, sequencing technologies evolve very rapidly. As a result, we have increasingly large amounts of data to manage, a need for increasing storage capacity, and an even more important need to develop tools for data manipulation.

What is microbiology? How do the increasingly blurred lines between basic and applied research affect the discipline? What economic, legal and institutional dimensions of the existing research infrastructure shape our ability to create a digitally integrated research commons? The issues that we are supposed to cover at this symposium are enormous.

I think I was asked to speak because I am a past president of the American Society for Microbiology (ASM). During the year I was president in 1990, almost 20 years ago, I did what was then considered a rather radical thing. I had a presidential symposium on the Human Genome Project. At the time, many microbiologists were against genomics, because they considered it “big science.” How times have changed!

In establishing the context for our Conference on the Microbial Commons, I have been asked to set the stage for our discussions about the integration of digital and physical resources for clinical and environmental microbiology.

The charge was so broad and so challenging that I have decided to focus on examples from clinical microbiology to the exclusion of the environmental. Furthermore, because one cannot talk sensibly about the future without talking about the past, I am going to start with some real basics. Many of you are not microbiologists, and perhaps may need the primer.

I went to the University of Chicago, where professors always said to go back to Aristotle—start with the definitions. When you look at definitions in our post-modern world, you should remember that the words also carry their connotations, so I begin with some of the definitions of "common" below, and then I follow it with definitions of "commons."

When we speak of “commons,” we generally are talking about the notion of shared public resources. If you are an educated person, it is very hard to use the term without the shadow of Garrett Hardin’s famous 1968 essay on the “tragedy of the commons.” This concept of the commons being associated with negative outcomes has entered the shared vocabulary of science, and I think the vocabulary of law. It occasionally even makes it into the popular press.

Now let me offer some basics for those of you who are not microbiologists. Microbiology is not small biology, but rather it is the biology of organisms that are too small to be seen by the naked eye. Microbiology encompasses the study of a whole array of life forms, especially a group that used to be called bacteria and that are now called the eubacteria and the archaea. Microbiology also deals with the study of viruses, protozoa, fungi, and algae.

The symbol of microbiologists traditionally has been that of the light microscope because of the dependence on microscopy to see individual microbial cells. The microscope often appears in the logos of professional societies. When you look under the microscope at bacteria, you do not see a great deal of morphology and this has always been one of the challenges of microbiology: Not only are the organisms small, but they do not look as different as, say, peacocks and ostriches do.

Among the biggest heroes of microbiology—and microbiology has many heroes—was Louis Pasteur, who refuted the theory of spontaneous generation. He proved that microorganisms are generated by other microorganisms. He also developed one of the first treatments for a microbial disease, rabies.

For infectious diseases, the hero was Robert Koch who first showed definitively that a particular microbe could cause a given infectious disease (anthrax). The experimental protocols he used are now called Koch’s Postulates. They are a microbiologist’s four-rule version of the Ten Commandments, done in a specified sequence to connect diseases with specific etiological agents.

An aside: I happen to believe that many chronic diseases such as heart disease and arthritis are going to have microbial connections, but this hypothesis is not going to be easy to prove by Koch’s Postulates. That is another story, however.

Although the study of infectious disease is what brings microbiology much of its fame and scientists much their funding, it is certainly not the positive, friendly side of microbiology. Microbiology has an image problem rooted in this notion that microbes are germs that are bad and that make us sick. Even though there are many “good microbes”

that have a positive economic impact in our lives, much of the study of microbiology is associated with its medical applications to infectious diseases.

Of course, there are many other microbiological societies outside the United States. The British have the Society for General Microbiology, which also publishes a number of premier journals and a magazine. Then there are dozens and dozens of microbiological societies associated with different countries, many of which also publish distinguished journals. Some countries have multiple microbiological societies focusing on clinical, environmental, or industrial aspects of the profession.

The International Union of Microbiological Societies (IUMS) was founded in 1927. The IUMS is an umbrella organization that attempts to provide a forum for all of these international societies. If a person is an IUMS representative from a smaller country like Peru or Israel, he or she will have an equal vote in kind of a United Nations of microbiological societies, which can lead to some interesting political alliances when the society meets every three years. The IUMS is subdivided into three congresses: bacteriology, virology, and mycology. The virology congress is the most active.

The IUMS and many of the national societies are associated with culture collections of microbial strains and materials. Culture collections are physical repositories of microbes (bacteria, molds etc) and their derivatives. Culture collections contain microbial materials, deposited by scientists, which are associated with the scientists’ publications and patent applications, or are used in teaching or for other purposes. The governing organization here is the World Federation of Culture Collections (WFCC). The WFCC in turn is associated with a major international biological organization, the International Union of Biological Sciences, as well as with the IUMS. The WFCC is concerned with the collection, authentication, maintenance and distribution of cultures of microorganisms. It provides liaisons, sets up information networks, organizes workshops and conferences, and publishes newsletters and other works.

The Federation watches over more than 450 individual culture collections from 62 countries, which vary enormously in size and capabilities. Here in the United States, for example, we have the American Type Culture Collection (ATCC) and the collection at the U.S. Department of Agriculture’s Northern Regional Research Laboratory (NRRL), both of which we will hear about later in the symposium, and a number of other collections. The size and the range of these collections vary, and many of them have been struggling constantly, from the time they were founded, to get the funding they need to keep going.

The WFCC has an extremely ambitious agenda. According to its website, it has taken on a variety of challenges such as standardization, the financial sustainability of collections, microbiology education and outreach, and intellectual property issues. Another project is the World Data Center for Microorganisms (WDCM) developed through the activities of Professor Skerman, University of Queensland, Australia, and his colleagues during the 1960’s. WCDM pioneered the development of an international database on culture resources worldwide. This data resource is now maintained at the National Institute of Genetics in Japan and its records contain information on the organization, management, services and scientific interests of the collections, as well as linked records containing lists of all species held.

Concerns such as adequate staffing and obtaining funding are a constant fact of life for culture collections. Many of the smaller culture collections run by individual scientists at universities are permanently shut down when the major investigators retire because of the expense of keeping the collections active.

As I mentioned before, I have been a cheerleader for genomics in general and, more recently, for fungal genomics in particular. My experiences in working on the steering committees of several fungal genome projects make me think that perhaps we should seek the common ground for the microbial commons in lessons learned from genome projects rather than in some of the treaties that have come out of international biodiversity concerns.

Microbiology and genomics have become very strong bedfellows. In fact, microbiology has played a central role in the development of genetics and molecular biology since the middle of the twentieth century. To offer a quick overview on the history of genetics, let me remind you that it was a microbiologist who first showed that genes were made of deoxyribonucleic acid or DNA. The so-called transforming principle was discovered in bacteria, and bacterial genetics soon superseded all the work that had been done with Morgan’s Drosophila flies, Mendel’s peas, and McClintock’s corn plants. That microbiologist was Oswald Avery, who did this wonderful research at the Rockefeller Institute during World War II. Once it was understood that DNA was the transforming principle, the discovery of the structure of DNA became a holy grail of biology. It was elucidated by Watson and Crick, who published the now-classic double-helix model for DNA in 1953.

The breakthroughs in genetics, many of which were nurtured in a microbial womb, continued to occur, but I will skip over most of them and go right to work that happened in the 1970s—the breakthroughs in recombinant DNA research and genetic engineering. Genetic engineering very rapidly led to many forms of commercialization. I have been told that there was once a meeting at which Paul Berg presented some of the early work on gene splicing, and some young fresh-faced person in the back of the room said, “Gee, there are practical things you could do with that.” In response, Berg deadpanned, “It never crossed my mind.” Unsurprisingly, basic research in gene splicing led rapidly to the first recombinant product, human insulin (marketed by Eli Lilly) after which microbiology and genetics became increasingly supported by venture capital.

Another important enabling technology is the polymerase chain reaction (PCR), which some people at the Cold Spring Harbor Laboratory have described as the genetic equivalent of a printing press. The key work was done by Kary Mullis, who worked at a biotechnology company, Cetus Corporation. The company no longer exists, but PCR certainly does, and Mullis would later share a Nobel Prize for his work.

PCR was coming of age at the same time that DNA sequencing became possible. When I was a graduate student, if you wanted to figure out anything about the content of a gene, you had to do it laboriously, working back from the amino acid sequence of proteins. At the time, many people did not think it was possible to sequence something as simple as the DNA molecule, which has only four different kinds of nucleotides. However, research by Sanger, Maxam, and Gilbert made such sequencing possible, originally using laborious radioactively labeled sequencing gels to determine the different bases in a large DNA polymer.

The U.S. government generously supported the human genome project from its beginning, and the first draft of the genome was finished faster and with more detail than anyone had expected. There were lots of surprises and they continue to this day. The field has become “big science.” When I was a graduate student, it was rare to see a biology paper with more than four authors, but now papers routinely appear with dozens of authors, as those of us who have been involved in genome projects well know.

Simultaneously, computers were adapted to the study of DNA. Among the high points in what is called “bioinformatics” were the founding of GenBank at the National Center for Biotechnology Information and the development of the BLAST algorithm. Several international groups have developed efficient methods for data storage and sharing that have transformed all of biology.

Now let me talk about the 21st century. Here is our charge: We are supposed to focus on improving the management of both the physical materials and the digital scientific literature and databases in microbiology. The reason for going through all this history is to show you that the field has more than a century of internationally diverse professional societies, traditions, mores, and ways of going about its work. It is not going to be possible to create a uniform new centrality out of this Tower of Babel.

Perhaps, however, we can do some civilizing around the corners. Remember that the physical materials we are talking about are largely those that are held in the culture collections. These living cultures consist of taxonomic type strains, the model strains used by geneticists, patent deposits, as well as a lot of derivative materials that come out of gene cloning and genomics research. There are also cell lines and there are phage splices. The culture collections that maintain these vast resources often have very different standards of quality control. It is also worth noting that the culture collections already are associated with digital resources, which also have varying accessibility and quality. There are some big issues concerning best practices here. Moreover, in recent years, following the anthrax scare, the U.S. federal government has been creating hurdles related to biosecurity. Finally, material transfer agreements raise many new issues within the research community. There was a time when you sent your money in to the American Type Culture Collection, and it sent you a culture. Or I could write to Cletus Kurtzman at the NRRL, and he sent me a culture at no cost. Those times are over.

A common estimate of how many microbes are known to science suggests that it is about one percent of all microbes on the planet. The existing estimate comes from various sources, but the important take-home lesson is that we are pretty sure we have not identified most microbes. As we go forward, we should be careful that we do not make it too hard to identify, study, and preserve the hitherto undiscovered microbes. Unfortunately, however, evolving regulations may be making the research on microbial systematics more difficult, not less. Some of the negative developments have arisen from various biodiversity treaties that focus on plant resources and from making sure that so-called less developed countries have access to the biological materials found in their countries. Such concerns have led to various restrictions on the collection of materials and data.

This raises an issue that it is sometimes hard to describe to people who are not scientists. What motivates scientists? Many of us work extremely hard. My husband comes from a Wall Street tradition and he does not get it. He says, “Why do you work so hard? You are not getting paid for this. You are not getting paid for that.” The reward structure of the scientific culture is hard to describe to outsiders, but a microbiologist friend of mine, Simon Silver, once over simplified it this way. He said that there are three kinds of people in the world. “There are money people, there are power people, and there are fame people.” Simon added that most scientists, including microbiologists, “are fame people.” In general, scientists gain their acclaim through publication in the peer reviewed literature.

Here are some more statistics. Between 1986 and 2006, journal expenditures of North American research libraries increased by a staggering 321 percent as libraries

expanded access to journals by licensing bundles of journals from different publishers.³ At the same time, the average journal cost increased by 180 percent, while the U.S. Consumer Price Index rose by 84 percent. In other words, journal costs have outstripped inflation by a factor of more than two. At Cornell University, the faculty senate passed a resolution in 2003 describing the cost of journals as “literally unbearable,” “unsustainable,” and “threatening to undermine core academic values.” The Cornell faculty pointed to the name of one commercial publisher in particular as a driver of these huge price increases.

With the development of the software that is used to bring the cost of publishing down, publishers no longer have to set type or do much else. Basically, the author does all of the preparation work for text and figures. The reviews are done free. Manuscripts are transmitted over Internet protocols. Yet commercial publishers reap the profits and charge these high subscription rates.

Simultaneously, as the online digital revolution has progressed, publishers have tried to adapt what has been done in print to the new environment. Free, open access publications add yet another challenge to the financial stability of scientific publishing. Scientific societies are fighting back in various ways. For instance, a number of microbiology journals are available free online six or fewer months after the release of the paper. The American Society for Microbiology has been a leader in this policy. Interestingly, although review articles are not as time-sensitive, you have to wait a year to get access to them.

The psychological impact of genomics is often expressed in metaphors. One of the few positive metaphors used is “wealth” often used in conjunction with the term “data mining.” More commonly, scientists describe being swept up in a “tsunami” of data. Other disaster metaphors include “explosion,” “avalanche,” “deluge” and “flood” of data. In summary, not only are researchers having trouble dealing with the legal, social, and economic aspects of the new biology, we also are having difficulty dealing with it intellectually. New technological systems regularly outpace our capacity to adapt.

I will conclude by mentioning a few major issues and organizations that we will be speaking about more in detail at this symposium. The Convention on Biological Diversity’s Article 15 on Access to Genetic Resources gives states sovereign rights over their natural resources, and provides that “the authority to determine access to genetic resources rests with the national governments and is subject to national legislation.”

Many unresolved issues arise from intellectual property treaties concluded at the World Intellectual Property Organization. Such agreements typically are developed to protect creative artists, such as the Beatles, not for microbiologists who need to access and reuse a broad range of digital and material inputs in order to conduct their research. Further, the World Trade Organization and its conventions are not developed by or for scientists. As a practicing scientist, I can attest to the fact that scientists often ignore the many newly imposed rules in exchanging microbial cultures across institutions or borders. If you can call a contact and get a necessary microbial culture for your research, you just do it informally and forget about the material transfer agreement. I have seen a statistic that some 60 percent of microbial cultures still are transferred this way.

Looking ahead at designing a microbial commons, I think our best hope lies in the fact that the genome sciences have done such a good job in developing an “-omics”

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³ See http://library.uic.edu/home/services/publishing-and-scholarly-communication/the-cost-of-journals

commons. GenBank has no restrictions on the use of its data. Furthermore, GenBank has cooperative agreements for the exchange of genomic data with groups in Europe and Japan, and I would not be surprised if we see open DNA databanks established in China and Korea in the near future. The European Bioinformatics Institute has great open source information. The Genomic Standards Consortium is working on doing research community outreach and developing common vocabularies. The notion of a common vocabulary is often referred to as a genomic Rosetta Stone. Such semantic interoperability will facilitate meaningful access to the information. Many geneticists are good at coming up with catchy names, and they consider the human genome as analogous to a periodic table of our genes.

Finally, to return to where I started, infectious diseases continue to emerge, and while it is bad news for humankind, these diseases make continued microbiological research essential—and fundable. Every time there is a major new human health problem it is more likely for governments to spend money on the relevant research. During my adulthood I have seen a number of diseases such as herpes and AIDS go from obscurity to prominence. Other emerging diseases such as SARS also have the potential to cause enormous harm.

Trying to end on a positive note, let me reemphasize that it is good that microbiology has entered the popular consciousness. Awareness of the need for a microbial commons will help ensure public support for our efforts. Nevertheless, we have our work cut out for us.

Reference: Hardin, Garrett. 1968, The Tragedy of the Commons, Science, 162:1243-1248