age of bioscience

Jim J. Bull, Ph.D. is the J. F. Miescher Regents Professor of Molecular Biology at the University of Texas in Austin. He works on problems of genetics and evolution, especially as they pertain to disease. He uses experiments to understand how viruses evolve in the presence of inhibitors, how they might be engineered to make safe vaccines, and whether bacterial viruses (phages) can be used to treat bacterial infections. 

• Evolution underlies many improvements in agriculture (e.g., the artificial selection of crop strains and livestock breeds).
•  A less well-known fact is that evolutionary principles were used to produce many of our best vaccines and that evolution also causes problems with the use of some of those vaccines.
• Some of the most promising areas for the future use of evolutionary biology lie in drug development and the biotechnology industry; patents worth vast amounts of money are based on ways of creating evolution (or avoiding evolution) in test tubes. 

Polio vaccine is an old example but it is a good one.

• The vaccine now used to immunize against the disease poliomyelitis is a live poliovirus that we eat.
• This live virus does not give us the disease (except to about 1-2 in a million people vaccinated) because it is genetically weakened so that our body can defeat it.
• This process of weakening is called attenuation, and it is an evolutionary process. The attenuated vaccine strains came from wild, virulent strains of poliovirus, but they were evolved by Albert Sabin to become attenuated. Essentially, he grew the viruses outside of humans, and as the viruses became adapted to those non-human conditions, they lost their ability to cause disease in people.

This method of attenuation has been used to create many live vaccines. Evolution was the good guy here because it helped us make the vaccine.

But the role of evolution and evolutionary biology does not end here -- evolution becomes the bad guy too.

• When a person eats the attenuated virus, it infects his/her gut cells and starts doing what viruses do -- making copies of itself.
• These viral progeny infect other cells in your gut, those in turn make other viral progeny, and so on, until you have a population of poliovirus growing inside your gut.
• Some of these viruses carry mutations, and some of those mutations (one or two in particular) restore most of the virulence to the virus.
• In your gut, these restored viruses may have a selective advantage over the weakened viruses, and in the course of a week or so after eating the vaccine, you begin shedding virus with restored virulence.
• In short, an evolutionary process inside your gut undoes Albert Sabin's attenuation of the virus. 

These restored viruses do not hurt the person taking the vaccine because by the time restored viruses get to be abundant in the gut, the immune system has enough of a head start to keep the virus from getting into the central nervous system. Disease is caused only if the virus gets into the central nervous system.

• However, if we were to vaccinate just one person in a population of non-immunized people the restored viruses shed from this one person would infect other people and could start an epidemic of nasty poliovirus.
• In fact, people have gotten the disease from people who were recently vaccinated.
• Fortunately, this problem caused by evolution has an easy solution -- when polio vaccine is first introduced to a community, we try to vaccinate everyone in the community at once.
• This is what happened in the U.S. when the Sabin vaccine was first introduced in the U.S. in the 1950's (vaccine "Sundays"), and it was done in other countries as well.
• The WHO did all of China in 3 days, and vaccinated 90,000,000 people in India in one day.
• Thus, understanding the evolution of poliovirus virulence allows us to use the vaccine without causing unnecessary disease.

The harm in misunderstanding evolution

The evolution of drug resistance in bacteria is one of the simplest examples of evolution that we have. It is extremely relevant to medicine. And since it is a case of microevolution, it is an example that should be widely embraced. Yet many people profoundly misunderstand drug resistance. Even news reports from the BBC have gotten it wrong. 

Bacterial resistance to antibiotics is an evolutionary phenomenon:

• heavy use of antibiotics selects bacteria that are genetically resistant to the drug
• with continued use of antibiotics, those resistant forms of the bacteria multiply and spread to other hosts
• eventually, resistant bacteria replace the population of once-sensitive bacteria. 

In the minds of some people, however, the problem with misuse of antibiotics is that it can lead to a physiological tolerance in the person taking the drugs, so that antibiotics are no longer effective in that person. That is, they think that drugs become ineffective because of the person, not the bacterium. This erroneous, non-evolutionary view has serious ramifications, because it can lead to an unwarranted complacency about antibiotic misuse. Because drug resistance is evolutionary, your neighbor's misuse of antibiotics can injure or kill you. The unregulated use of antibiotics in, say, Europe can bring strains for which we have no defense to the U.S. and our hospitals. It is not simply a matter of the proper use of antibiotics in each of us individually; it is a matter of everyone's proper use of antibiotics. 

It is tempting to speculate that the common, though not universal, public failure to understand the evolutionary basis of drug resistance reflects a widespread ignorance of evolutionary principles, even principles professed to be uncontroversial. The fact that this misunderstanding is not confined to the western side of the Atlantic suggests that political opposition to the teaching of evolution is not the only cause.

Modern applications of evolutionary biology

There are numerous ways to apply evolutionary biology to our needs today, among them:

• prolonging the life of drug/chemical resistant compounds
• constructing evolutionary trees
• pathogen tracking
• industrial production of biochemicals and other agents

1. Drug resistance and chemical resistance in microbes, plants, and animals.
In the latter half of this century, industry has been exceptionally good at providing compounds to kill viruses, bacteria, insects that eat crops and weeds that grow in crop fields. We even have an abundance of chemotherapy drugs to kill rogue cancer cells. Yet virtually without exception, our attempts to kill these organisms cause them to evolve resistance against the chemicals used to kill them. For example:

• Isolates of the AIDS virus with up to 15 different drug-resistance mutations are known, and the latest drugs are becoming ineffective.
• Some strains of bacteria are resistant to all available antibiotics.
• For multi-drug resistant tuberculosis, surgery is the only cure because antibiotics don't work and only 50% of those infected survive.
• Chemotherapy for cancer often fails because drug-resistant cells evolve during treatment.
• Pesticide resistance and herbicide resistance is so common now that the financial incentive to make new pesticides and herbicides is break-even or worse. 

Evolutionary biology suggests how best to prolong the useful life of drugs/chemicals. The amounts of chemicals used, what combinations of chemicals to use, and when to apply them are all questions that can be assessed from the perspective of preventing or slowing the evolution of resistance. In some cases now, the companies marketing the compounds have a financial interest in maintaining the longevity of their product, and they are funding studies by evolutionary biologists to develop wise use protocols. In other cases, however, economic and emotional forces dictate policies that speed up the evolution of resistance (e.g., patients demand and physicians write prescriptions for antibiotics for viral infections; antibiotics are used in animal feed). 


2. Evolutionary trees
Perhaps the core of evolutionary theory is that all life forms are connected to each other through common ancestry. Molecular biology has reinforced this view to a far greater level than was deemed possible even 50 years ago. On a short time scale, of course, we observe that this is true - everything alive comes from something else that is both alive and similar. One of the big developments in evolutionary biology over the last 2 decades is a methodology to estimate the underlying patterns of ancestry among living things. These reconstructions of evolutionary history are known as phylogenies, or phylogenetic trees, because they are branched somewhat like trees when drawn from bottom to top. We can use molecular data to estimate the common ancestries of life as far back as we like -- for example, between bacteria and our mitochondria (the energy-producing organelles in our cells). But we can also use these methods to estimate much more recent ancestries. And these methods have found many worthy uses in tracking infectious diseases.

3. Molecular epidemiology -- pathogen tracking
To an epidemiologist studying infectious diseases, it is very useful to know how or where a person became infected with the disease. This information is perhaps the most basic fact we can use in preventing the further spread of a disease. For over a decade now, epidemiologists have been using DNA sequences of viruses to make phylogenetic trees and thereby track the sources of infections. Some of these examples are spectacular.

• Law: A case of intentional HIV injection? In a highly publicized case in Lafayette, Louisiana in 1998, a woman claimed that her ex-lover (a physician) deliberately injected her with HIV-tainted blood (HIV is the virus that causes AIDS). She did not know whose tainted blood it was nor did she realize she had been injected with blood until she became sick with viral infections months later. Records showed that the physician had indeed drawn blood from an HIV+ patient on the day she was injected. There were no records of her injection and no witnesses. So how could her story be tested? Evolutionary trees provide the best scientific evidence in a case like this.
• HIV picks up mutations very fast - even within a single individual.
• If one person gives the virus to another, there are few differences between the virus in the donor and the virus in the recipient.
• As the virus goes from person to person, it keeps changing and gets more and more different over time.
• Thus, the HIV sequences in two individuals who got the virus from two different people will be very different.
• Thus, if the woman's story were true, her virus should be very similar to the virus in the person whose blood was drawn but should be very different from viruses taken from other people in Lafayette.
• That was exactly what the evolutionary trees showed; her virus appeared to have come from the patient's virus but was unlike the virus taken from other people in town.
• Since there was no way to explain how she would have gotten THAT patient's virus on her own, the evolutionary analysis supported her story. (Incidentally, this case was the first use of phylogenetics in U.S. criminal court.)
• Did a Florida dentist with AIDS transmit the virus to his patients? Kimberly Bergalis made national headlines and testified in congressional hearings as a heterosexual young woman who got AIDS. The only known potential source of her virus was her dentist, and over half a dozen of his other patients also had the disease. In this case, the initial evidence implicating the dentist was merely the statistical association of several people with AIDS whose only known exposure was the dentist. Again, evolutionary trees were created to see if the patients' viruses appeared to have descended from the dentist virus.
• The dentist virus did appear to be closely related to many of the patient viruses, as if it was the source.
• However, two patients appeared to have gotten their virus elsewhere, and those two patients were the only two infected patients with other risk factors.
• So again, the evolutionary analysis provided a critical means of understanding HIV transmission.
• Other cases: Evolutionary trees have been used in many other cases of infectious disease transmission.
• They were used to identify deermice as the source of hantavirus infections in the Four-Corners area in the early 1990s.
• They are routinely used to determine the source of rabies viruses in human cases, and they led to the discovery of a case in which rabies virus took at least 7 years to kill a person (a length of time far in excess of anything known previously).
• And trees have been used to determine whether recent cases of polio in North America were relict strains from the New World, were vaccine strains, or were introduced from Asia. 

4. Industrial production of biochemicals and other agents
"Directed evolution", i.e. artificially-induced evolution, has become part of the jargon in biotechnology:

• Artificially evolved enzymes and other proteins are soon to become part of household and medical technologies.
• We will have protein-based drugs that, unlike the proteins inside our bodies, degrade slowly so that we don't need to take so much of them.
• Enzymes are being evolved to work in detergents (which they don't normally do).
• And as the stuff of futuristic novels, molecules are being developed to bind anthrax spores, ricin molecules, and other potential bioterrorism agents.

All of these developments take advantage of one or more forms of test-tube evolution. Armed with a knowledge of how natural selection works and combined with the right kinds of laboratory technology, people can create molecules to perform seemingly any kind of function. In some of the more spectacular cases, these test tube evolution methods have created enzymes from purely random pools of DNA (or RNA) sequences. Even 10 years ago, it was thought that a DNA enzyme was impossible, yet armed with only an understanding of how to apply test tube evolution, a DNA enzyme can now be created in days. 

In conclusion

The pace of evolutionary biology and its ramifications has outstripped public awareness as well as expanded beyond the knowledge base of most classical evolutionary biologists. Even the textbooks have not kept up. It is thus difficult but important to recognize that evolutionary biology has implications to a new century of medicine, agriculture, biotechnology, and even law. Students educated with this knowledge will have an edge in the competitive job markets of the future, but at least in some areas of medicine, a basic public understanding of evolutionary principles may be essential in successfully waging the ongoing war with infectious diseases.

 

Applied Evolution: 
Technology for the 21st Century


Visions of the 21st Century: Science And Space
Time Magazine Online (April 10 2000) offers 17 articles about the future, e.g., "Will we keep evolving?", "Will we have a final theory of everything?", and "Will there be anything left to discover?"
http://www.time.com/time/reports/v21/science/index.html

Scientific Breakthroughs Spawn Optimism about Future Research
A news story about how scientific advances have prompted predictions of a 'Golden Age' in biomedical research.
http://www.laskerfoundation.org/fundingfirst/comment/15/comm1.html

Lateline (Australian Broadcasting Corporation)
Hear the interview "A Brave New World" conducted on 12/11/98 with three great scientific minds about what we can expect from science in the 21st century: Sir John Maddox, author, "What Remains to be Discovered"; Professor Paul Davies, author, "The Fifth Miracle" and Professor Michio Kaku, author, "Visions".
http://www.abc.net.au/lateline/stories/s17000.htm

The Third Culture
Read chapter 4 of "The Third Culture: Beyond the Scientific Revolution" by Brian Goodwin, biology professor, reprinted here online to consider the author's view of the future of biology.
http://www.edge.org/documents/ThirdCulture/k-Ch.4.html

Read a book
Gene Future : The Promise and Perils of the New Biology by Thomas F. Lee
An examination of where we are going, where we should go, and where we dare not to go with the knowledge revealed by the "New Biology."

"The public understanding of science" survey
Participate in a short survey about your interests and knowledge of science. The survey began in Jan. 2000 and you can view the results to date. The questions are worded in poor, but understandable, English because the text was translated from Greek by the organization conducting the survey.
http://hyperion.math.upatras.gr/survey/pus/index.html