Ch 1.  What is Biology?

bi·ol·o·gy NOUN: 1. The science of life and of living organisms, including their structure, function, growth, origin, evolution, and distribution. It includes botany and zoology and all their subdivisions. 2. The life processes or characteristic phenomena of a group or category of living organisms: the biology of viruses. 3. The plant and animal life of a specific area or region. – The American Heritage Dictionary

Biology is technology.  Biology is the oldest technology.  The dictionary hints at this definition with reference to the many interactions that characterize an organism or a biome, but life makes it explicit through behavior.

Technology is usually thought of as material or methods derived solely from human hands, often explicitly linked with industry and the economy.  It is certainly true that human society as we know it today is built on a currency of tools and ideas.  But it is time that we recognize this definition as overly constrained.  The conceit that humans are the only species capable of purposefully manipulating their environment is quite thoroughly put to the lie by myriad examples of animals that use tools, from chimpanzees, to otters, to crows.  In many cases, it is clear that tool building skills in animals are passed from generation to generation.  It is plainly evident that tool use is widespread throughout the animal world.

But extending the definition of technology to animal tool cultures is still too limiting.  Beyond physical manipulation of macroscopic objects, organisms and the molecules that constitute them can be thought of as technology as well.  The bits and pieces of life are technology every bit as powerful and flexible as tools created by animals and humans.

Throughout the history of life on this planet, various organisms have made use of other organisms in sophisticated ways.  Early on in this history, without any intent and entirely by chance, the ancestors of both plants and animals co-opted free living organisms that became what we now call mitochondria and chloroplasts.  Those organelles provide energy to their host cells, and these symbioses now support much of the life on this planet.

The technological aspects of biology in fact go much deeper, to the very molecules that underlie life itself.  Deoxyribonucleic acid (DNA) is the molecular repository of the instructions required to build any organism.  While the DNA describing how to build “higher” organisms such as humans is basically static over the lifetime of an individual (save mutations or alterations due to viruses), bacteria alter their genomes through the exchange of small circular bits of DNA, packaged in stable, circular elements called plasmids.  Plasmids are extraordinarily useful bits of technology, a kind of standard packaging for DNA, that I will return to time and time again in this book.  Plasmids can serve as the medium for transfer of useful genes, such as those for antibiotic resistance, between individuals, and can be passed along to offspring.  Humans have for decades made use of this packaging by applying a high voltage jolt to open temporary pores in microbes through which plasmids can migrate.  But it has recently been demonstrated that humans have merely reinvented this trick, known as electroporation.  Certain soil-dwelling microbes are particularly likely to take up plasmids from the environment after lightening strikes [1] , a trait that enhances their ability to sample the myriad DNA sitting around in the environment and thus pick up genes that, if they are fortunate, are useful.

Yet more sophisticated are natural schemes to respond to particular threats in the environment.  The genome of Vibrio cholerae, the organism that causes cholera, contains in its chromosome another sort of DNA packaging technology, Integrated Conjugative Elements (ICEs), which contain genes that confer resistance to particular antibiotics.  The remarkable thing about this technology is that exchange of these ICEs between bacteria is inhibited except when those antibiotics threaten the bacteria [2] .  This phenomenon seems quite contrary to the common, and evidently naïve, belief that microbes are simple beasties subject solely to the whims of the environment.  With a little reflection, it is clear that there is significant evolutionary pressure on microbes to develop defenses against human attacks.  Prior to 1993, the particular ICE in asian V. cholerae strains was not found in nature.  It is now present in almost all clinical isolates in Asia.  Of specific interest (and perhaps worry) in this case, the bacteria have developed a mechanism whereby the presence of ciprofloxacin promotes the spread of antibiotic resistance genes [2] , which accounts for the wide distribution of ciprofloaxacin-resistant cholera infections.  This economy of genetic material, while by no means intentionally managed by microbes, encompasses a set of tools that allow organisms to adapt to, and even manipulate, environments that would otherwise be fatal.

            Ultimately, however, we humans are the most successful organism on the planet when it comes to using biology as both tool and raw material.  We have, intentionally or otherwise, manipulated many species of plants, animals, fungi, and bacteria for thousands of years.  It is now clear that humans cultivated corn at least 9000 years ago, selecting plants with useful (or tasty) random genetic changes, combining those mutations into a single plant via breeding, and then propagating its seeds [3] .  Even with this relatively sophisticated genetic manipulation, we are certainly late to the game; other organisms have been at it far longer.  Yet humans make use of a greater diversity of species than any other organism on earth.  This reliance has long nourished both the human body physical and the human body social.  It is unlikely we will find an alternative to this habit any time soon, even if we actively sought it.

If this history is any guide, human society will in coming years become even more entwined with biology.  Our economy will lead the way.  Most human technological processes and products become more complex with time, and generally more capable along the way; technology based on biology will proceed similarly.  In the mid 1970’s, researchers developed techniques to modify single-celled organisms to produce therapeutic drugs.  While various means had previously been used to randomly mutate genes, this was the first intentional direct genetic modification of other organisms by humans.  What was cutting edge technology three decades ago is today routine in university lab courses, and has already been included in some high school curricula.  While simple modifications of single-celled organisms are now commonplace, the cutting edge has, of course, moved.  Today, academic and industrial researchers alike are working with multi-cellular organisms, contending with the attendant increase in biochemical and developmental complexity.  Goats and cattle have been modified to produce milk containing complex proteins for novel materials and pharmaceuticals, while viruses can be used to reprogram mammalian cancer cells to invite attack by the immune system, thereby curing the disease.  The latter example is made possible by the ever improving knowledge of molecular biology and the ever improving technology used to manipulate molecules.  The potential therapy follows a strategy outlined by Judah Folkman in 1971 [4] , when he suggested that one way to cure cancer was to figure out how to prevent blood vessels from nourishing a tumor.  Scientists and physicians are exploring many different approaches to accomplish this goal.  Alan Garen and his colleagues at Yale University described in 2001 an elegant implementation of the idea, to which I will shortly return.

The underlying insight behind Folkman’s suggestion was straightforward.  Tissues require oxygen and food, tumors included.  These nutrients are provided by the circulatory system, and cancerous cells produce chemical signals that prompt blood vessels in their vicinity to proliferate and provide a rich environment for tumor growth.  However, unlike the vasculature in healthy tissue, blood vessels in tumors tend to be leaky.  Garen’s approach to cancer treatment cleverly exploits this back door.

 The key to the potential treatment is a new protein, one end of which binds to proteins exposed by the leaky vasculature, the other end of which is a flag that incites attack by the immune system.  Because it consists of two proteins conjugated together, Garen called the new entity an immunoconjugate molecule, or “icon” for short [5] .  The sneakiest part of the treatment is the way Garen decided to put icon into the tumor.

The procedure relies on a virus whose genome has been replaced by new instructions.  Specifically, the genetic instructions that allow the virus to replicate have been replaced by the instructions to make icon.  Thus rather than producing many copies of itself and proliferating throughout the host, the viral genome directs host cells to follow these new instructions.  When injected into a tumor, these instructions coerce a cancer cell to produce icon, which with the help of the immune systems destroy tumors from within.  Such radical change in the ability to alter the course of disease is a mere hint of the prospects of biology to influence the state of human existence.  At last report, this technology should enter human trials in 2005.

Medicine is only one arena of potential, and one with an abused reputation at that.  In recent decades, there have been many unmet promises that molecular biology will revolutionize health care.  These promises are in general not over-reaching so much as premature.  We simply have much more to learn before those promises come to fruition.  Technology is a process, and a body of knowledge, as much as a collection of artifacts.  Biology is no different.  We are just beginning to learn enough to comprehend the challenges inherent in the next stage of biology as a human technology.  Current rapid progress is due to advances in two endeavors, the science of biological systems and the technology used to manipulate them.  The two efforts are, of course, completely intertwined.

Indeed, the difference between the organisms we depend on and the technology we use to manipulate them is quickly disappearing.  We have progressed so far that we use molecular tools, themselves first discovered in microorganisms, to read the basic instructions of life one letter at a time.  We then rewrite those instructions, drawing from a library of molecular elements gleaned from different organisms, stitching together words uncovered in previous reading.  The new instructions are implemented inside a cell to produce the next generation of molecular tools.  Skills used in creating novel genetic instructions will become ever more subtle, the weave of new words ever finer, as we master the grammar governing systems of genes.  This increasing ability to edit life’s control algorithms, re-directing biological systems to new tasks, will undoubtedly soon extend to biology’s own enviable ability to manipulate inorganic matter.  The professional and popular scientific press are abuzz these days with new details about how biological systems produce materials such as bones, shells, and webs.  Given the diverse classes of materials manipulated by biological systems, from carbon, to silicon, to metals, scientists and engineers around the globe hope to coax biology building objects designed by humans.  There are already efforts underway to fuse biological and electronic systems, raising the possibility of a true interface that enables unprecedented communication, and control, across the boundary between animate and inanimate.

Such fine manipulation of the biological world requires greater facility than humans now possess, but the technology we use to manipulate biological systems is changing very rapidly.  This has been many years in coming.  We are in the midst of realizing capabilities first forecast more than fifty years ago.  The development of x-ray crystallography and nuclear magnetic resonance in the decades before 1950 opened a window to the molecular world, providing a direct look at the structure of natural and synthetic materials.  Similarly, during that same time period the elucidation of information theory, cybernetics, and basic computational principles set the stage for today’s manipulation of information.  Biology is the fusion of these two worlds, where the composition and structure of matter determines its information content and computational capabilities.  This description may also be applied to computers, but biology is in addition a state of matter, if you will, whose interaction with the laws of physics allows self-editing and self-propagation.  It is no surprise, then, that given our improving abilities to measure and manipulate molecules on the one hand, and to apply powerful computational techniques to understand their behavior on the other, that biology is today consuming considerable attention.

The effort to improve our understanding and manipulation of biological systems is in fact now pushing technological development in other fields.  Where supercomputer design was once driven by the need for machines better able to simulate the detonation of nuclear weapons, supercomputers are now designed and built with the express purpose of simulating mathematical models of biological system.  The data for these simulations comes from expensive, sensitive tools that can measure the miniscule forces between two individual molecules, from less precise instruments that can assay the activity of thousands of genes in parallel, and from gene sequencing.

Whether mathematical model, laboratory instrument, or molecule, these “biological technologies” will soon enable a very different use of biology than has occurred in the past.  Measurement will improve, quantitative models will improve, and the give and take between them will result in true design and engineering of biological systems.  Today’s science and technology provides a mere glimpse of what is in store, and we should think carefully about what may happen just down the road.

The Societal Impacts of Advances in Biological Technologies

Just as the study and manipulation of biological systems are ongoing processes, so is the popular understanding of the consequences of those actions continually changing.  Unfortunately, public conversations about manipulating biological systems, about regulation, and about societal impacts, are informed less by the challenges ahead than by today’s scientific headlines, sometimes stretched to fit the front page of tabloids.  Moreover, the (imperfect) rendition of science presented by the press is subject to just as much manipulation to influence sales as every other topic that appears in the media.  But there is a more general, intrinsic problem with the way science is presented to the public.

By the nature of the modern scientific process, most results reported in the press are already behind the state of the art.  That is, the press reports the past, not the future.  Scientific papers are submitted for publication months after work is finished, go through a review and editing process consuming additional months, finally appearing in print many months after that, all the while being surpassed by continued research.  Given the pace of technological improvement, and consequent increased capabilities in the laboratory, more and more new science is being squeezed into the time between discovery and publication of old results.  While the popular press reports a small fraction of this science prior to its appearance in academic journals, the vast majority of scientists follow the accepted practice of avoiding pre-publication press releases.  Some prestigious scientific journals even refuse to publish results that have appeared in newspapers, new magazines, or on television or radio.  The last three decades have seen press frenzies surrounding cold fusion, various cancer cures, infectious diseases, and human cloning, not to mention various cases of alleged scientific misconduct.  These stories are often completely blown out of proportion, with the professional reputations of participants sometimes irreparably damaged through no fault of their own.  With these examples fresh in memory, most scientists will prefer to keep out of the spotlight until their results are firmly demonstrated.  As a result, the gaps between discovery, disclosure, and discussion will continue to widen.  Thus scientific results, for good and bad, will continue to be presented to the public as fait accompli.  This is a systematic feature of the interaction of science and society that must either be changed or accepted.  Often sheer surprise can play as great a role in public responses as the science itself, not always to the benefit of scientists or to the funding and acceptance of the subjects they study.

The general public has played too small a role in the whole process of scientific discovery and technology development.  This is as true in biology as any other field.  Many scientists assume their greater knowledge of biological details puts them in a default position of leadership.  But this leadership implies a responsibility to the public at large.  Scientists need to do more to communicate the aims and implications of their efforts.  Yet there is also room for improvement in the behavior of the public.  As stakeholders, and as benefactors of scientific and technological advances, the public needs to work harder to understand the consequent risks and benefits of both action and inaction.  Of course, “the public” is composed of subgroups that will evaluate differently those risks and benefits.  Maintaining a healthy democracy requires recognizing these groups, including their perspectives in the debate, and forming a consensus from the mix.

Without a doubt, scientists should take the lead here, but it is no easy task.  James Watson, co-discoverer of the structure of DNA, puts it thus: “It is far better to tell it as it is and take the risk.  We should expect a constant concern from society as to where our knowledge is leading and whether to deploy it.  That certainly existed in the past, for instance in the opposition to automobiles.  But once you put someone in an auto you won't get them on a horse.” [6]

There is risk both in communicating with the public – the risk to which Watson refers – and in the decision to move in any technological direction or ask any question.  It seems a truism that no action is without risks, and a balance of risk and benefit lies at the heart of all rational decision making.  The prerequisite for rational risk analysis is adequate information, and herein lies the crux of our difficulties.  Despite public demands for more inclusion in deciding the course of science, scientists can do no more than pass along what is currently known.  Alas, even the most comprehensive attempts at producing better communication between scientists, politicians, and various interest groups in the public will always fail to completely satisfy.  Science by definition takes place at the edge of what is known, and thus at the edge of what is explainable in familiar terms.  “Telling it as it is” can simply add to confusion and apprehension.  It can take time for scientists to agree on a description of newly discovered phenomena, with public understanding of goals, risks, and benefits left wanting in the meantime.

Underlying Watson’s remark about risk is the issue of choice.  He has considerable faith that when shown the benefits of biological technologies, the public will choose the benefits despite unknown risks.  Moreover, he is certain that everyone agrees that automobiles are preferable to horses.  This assumption is manifestly incorrect for some populations in the U.S., whose members strongly prefer horses.  Watson’s assumption has never even been tested in some regions of the planet; the majority of living humans do not yet have the option to choose a car, and many cannot afford a horse.  In other words, given the choice of benefits and risks, some people will always choose to forgo the benefits, and even the most comprehensive efforts to communicate and forge consensus will fail to reach those unprepared to understand the question.  The process of science cannot help but leave a significant fraction of the public unsatisfied.

To make matters worse, the pace of science and technology, and the methodology of scientific planning and publication, contribute to an unnecessary air of secrecy that exacerbates public insecurities.  Successes, failures, and mistakes all appear as exclamation points in both the professional and popular media.  There is often little or no discussion of the motivation for, or history of, the work being reported, and the public is left demanding to take part in a decision making process that has already concluded.  Given the potential impacts of biological technology on all of humanity it is no wonder that there is an outcry over the way decisions have been made.  Future debates must be conducted differently, or the pace of science and technology will increasingly supersede discussion, leading only to more public dissatisfaction, criticism, and alarm.

Current concerns expressed by the public are, of course, not without merit.  The recent history of modifying biological systems has been characterized by fits and starts. Trials of genetically modified crops and human gene therapy have both met with mixed results, the former tallying up a failed effort with cotton, which resulted in significant economic loss to some farmers involved, and the latter at least one human death and several cases of leukemia in children.  Then there are the various mistakes with genetically modified corn finding its way, despite assurances that it wouldn’t, into the food supply.  Fundamentally, these and other efforts at modifying biology are hampered by a lack of understanding of existing systems.  It is simply not yet possible to predict the behavior of the vast majority of complex biological systems, from bacteria to ecosystems, let alone the affects of modifying them.  The near future of biological modification will continue to reflect this limited understanding.  Moreover, working with biology can be quite slow.  Some experiments require years of preparation and planning; others require years to gather data.  Yet as we shall see in the following chapters, the development of new mathematical, computational, and laboratory tools will facilitate the building of things with biological pieces – indeed, the engineering of new biological artifacts – up to and including new organisms and ecosystems.  The rest of this book explores how this is likely to transpire.  But first we have to understand what engineering is.

References:

1.         Ceremonie, H., et al., Isolation of lightning-competent soil bacteria. Appl Environ Microbiol, 2004. 70(10): p. 6342-6.

2.         Beaber, J.W., B. Hochhut, and M.K. Waldor, SOS response promotes horizontal dissemination of antibiotic resistance genes. Nature, 2004. 427(6969): p. 72-4.

3.         Fedoroff, N.V., Agriculture. Prehistoric GM corn. Science, 2003. 302(5648): p. 1158-9.

4.         Folkman, J., Tumor angiogenesis: therapeutic implications. N Engl J Med, 1971. 285(21): p. 1182-6.

5.         Hu, Z. and A. Garen, Targeting tissue factor on tumor vascular endothelial cells and tumor cells for immunotherapy in mouse models of prostatic cancer. Proc Natl Acad Sci U S A, 2001. 98(21): p. 12180-5.

6.         Wade, N., DNA, the Keeper of Life's Secrets, Starts to Talk, in The New York Times. 2003: New York.

Robert Carlson, Copyright 2005