Association AffairsPRESIDENTIAL ADDRESS

Passions

Science  09 Dec 2011:
Vol. 334, Issue 6061, pp. 1362-1366
DOI: 10.1126/science.1213199

What is the secret to success in science or anything else? Hard work alone is not enough. It is being passionate about something, enough to make a whole-hearted commitment of creativity, rigor, and determination. Let me share my lifelong passions. Foremost, I am passionate about investigating viruses and finding ways to control their growth. Along the way, I have also developed other passions: using science to build international bridges, improving science education, and maximizing access to science for diverse populations, especially women and minorities. I have sometimes wondered why these three issues have attracted me. Perhaps it is because social justice, fairness, and access to opportunities were the ideals that caused my family to make the United States our home. I have embraced my passions, and they have richly rewarded me.

A Passion for Viruses

Viruses first entered my life when I was exposed to electron micrographs of beautiful, symmetrical creatures that could not be seen by the naked eye but only through powerful microscopes that magnified images 40,000 times or more. When I started working with viruses in the early 1960s, very little was known about them. They were primitive life forms, consisting of either DNA or RNA as their genetic information, plus proteins and sometimes lipid envelopes with glycoproteins. They replicated only when they were inside cells. The details of how viruses enter cells and how they take over the cellular machinery were unknown.

It was the beginning of a golden age of virology when, as a graduate student, I chose vesicular stomatitis virus (VSV) to study as a prototype for RNA-enveloped viruses. VSV naturally infects horses, cattle, and swine. The disease, first reported in 1862 during a Civil War campaign in the United States (1), appeared as explosive epizootics during the past century. Bob Wagner, my thesis adviser at Johns Hopkins, used VSV in his laboratory as a sensitive tool with which to assay for interferon. Moreover, the virus grows readily in cell cultures to high titers, and its replication cycle is only about 5 hours. These properties made it seem like a good system to work on.

We soon discovered that VSV contains a single strand of RNA packaged with four proteins, two of which are phosphoproteins, all of which are encased in a lipid membrane containing polymeric copies of a glycoprotein (24). Inside cells, VSV produces five mRNAs that are complementary to the viral RNA found in the virus particle (5).

That presented us with a conundrum: Cells were not known to have RNA-dependent RNA polymerases, so where was the enzyme that could synthesize the viral mRNA? We sought and found a viral particle-associated enzyme that performs the necessary task (6). This led to the identification of a whole group of animal viruses, including rabies, measles, and influenza.

While working on the molecular biology of VSV, I read about a phenomenon described by von Magnus in 1954 (7), in which cells infected by dilute preparations of influenza virus produce more infectious virus than cells infected by undiluted or concentrated preparations. This was an unexpected result, since starting an infection with many viruses should produce more progeny. I decided to see if I could reproduce the von Magnus phenomena using VSV instead of influenza virus and it worked.

When the products were examined by electron microscopy, the two different methods of growing VSV produced two very different kinds of progeny. When the dilute virus preparation was used, the progeny consisted of bullet-shaped particles with a rounded end and a flat end. Undiluted inocula produced much smaller particles (Fig. 1) (8). On closer examination, they were like the bullet-shaped particles but shorter or truncated. This became the “Eureka!” moment for me. After seeing these purified particles under the electron microscope, Jack Greenawalt, the Johns Hopkins professor who showed me how to use the electron microscope, and I celebrated with beer.

Fig. 1.

Bullet-shaped (B) and truncated particles of VSV.

Fig. 2.

Single-stranded RNAs found in standard and DI particles.

Because of the difference in size between the two viral particles, each could be purified and then studied quantitatively in combination or as separate entities. Indeed, such experiments revealed that the truncated particles needed the infectious virus in order to replicate, but they interfered with the growth of infectious virus (9). Because of that, they were named defective interfering (or DI) particles. From numerous quantitative studies, it became apparent that the standard and DI particles have a predatorprey relationship (10). This cycle continues as virus spreads in cell culture or in tissues of an infected animal until the balance is perturbed by immune modulators or other viral inhibitors (1113).

How does inhibition by DI particles occur? The answer came from detailed examination and sequencing of the ends of the single-stranded RNAs found in standard and DI particles (14, 15). The ends of standard RNA contain untranscribed regions of approximately 45 to 48 nucleotides, which we label T and R prime; they represent different binding sequences for polymerase complexes that control transcription (T) and replication (R) of the viral RNA. Similarly, the truncated particles contain shorter RNA that are deletion mutants of the RNA of standard virus. In addition, the ends of DI RNA contain translocated sequences where T is replaced with R. These R and R′ complementary sequences at the ends of DI RNA not only form duplexes with each other, but can also fold up on themselves, resulting in panhandle- or hairpin-like RNA structures at the ends of the viral RNA (Fig. 2). Rearrangements in which the T sequence is replaced by an R sequence suggest a competitive advantage for the replication of the DI particle over standard virus.

Most viruses produce their own specific DI particles, many of which contain multiple polymerase binding sites and/or sequences that have increased their binding affinity for polymerases. Could DI particles ever be harnessed as vaccines or used to inhibit ongoing viral infections? I suggested the possibility of using viral polymerase binding sites to prevent viral infections by vaccination or to ameliorate infections by direct interference (16, 17). Lending strong support to this hypothesis are two recent publications (18, 19). Influenza DI particles protect ferrets from influenza. A small decoy RNA molecule with a hairpin structure containing binding sequences for influenza polymerase and its complementary sequence at either end, similar to our R and its complementary R′, was synthesized. When chickens were made transgenic for the polymerase binding sequences with this decoy RNA, they could still be infected but failed to pass on the infection to uninfected chickens. The authors suggest that decoy RNAs might contribute to infection control within a species or between different species for other virulent viruses as well.

Besides binding polymerase, double-stranded termini formed by these small RNAs might play additional roles such as inducers of innate immunity (20). Thus, continued sequencing and further studies on the mechanisms of single- and double-stranded viral RNA-protein interactions may provide a whole new paradigm for the control of diseases caused by viruses.

In addition to the DI work, my laboratory continued its focus on the basic biology of VSV. Most intriguing is a finding of phenotypic mixing between enveloped viruses, first shown by Choppin and Compans (21) and Závada (22) with VSV. Coinfecting cells with two different enveloped viruses results in a mixture of progeny, some with envelopes completely resembling the parental viruses but others with envelopes containing either a mixture of glycoproteins or completely covered by the glycoproteins of the opposite parent (Fig. 3). As the outer coat determines the binding of virus to host cell receptors, having new proteins on the viral coat makes these hybrids like wolves in sheep's clothing. They have been called pseudotypes.

We extended these findings to retroviruses (23), including human immunodeficiency virus (HIV) (24), and to DNA enveloped viruses (25). We found that the DNA-containing herpes simplex virus (HSV) is more efficient in donating coats than any of the other viruses that had been tested. AIDS patients are often found to be infected with other infectious agents besides HIV, particularly with herpes viruses. The disease-relevant question is whether HIV picks up a herpes virus coat, thus making it capable of extending its host range beyond CD4-positive cells. We, as well as others, have suggested that cooperative interactions between different viruses within one host may play a more important role in pathogenesis than previously realized (24, 2626). Irrespective of relevance to pathogenesis, pseudotypes have become important in themselves as powerful laboratory tools to stabilize viral vectors, usually made with retroviruses, and deliver these vectors to specific cells within an animal.

Fig. 3.

Pseudotype formation in VSV.

So, our pioneering work on the model VSV system demonstrates many of the first principles of viral replication, macromolecular synthesis, and limitations to viral spread and virulence. We have provided important tools through the pseudotypes and DI particles for studying virus transmission and virulence.

For the rest of this paper, I shall discuss my passions outside of scientific investigations. But as you will notice, they do relate to science and the life of a scientist.

Building International Bridges

I have been privileged to associate with many scientists from this country as well as internationally and host them in my laboratory. One of my first postdoctoral fellows was an Argentinean named Eduardo Palma. When he returned home, we continued to collaborate, supported by a joint National Science Foundation (NSF) grant that encourages international cooperation. One of my colleagues at Harvard Medical School asked how I could associate myself at that time with a scientist from a country governed by an autocratic dictator who had caused those who challenged his regime to disappear. It never occurred to me that I should not interact with Eduardo. Science, to me, is a universal language knowing no boundaries or any political differences. Since then I have had many interactions with foreign entities, first with individual trainees in my laboratory and later with governments. In fact, I am still practicing this kind of one-on-one science diplomacy that many scientists experience.

So what is science diplomacy? It is about building relationships between different countries and cultures through science. This can occur at many levels involving governments, institutions, and individuals. The exchange of scientific information can help underdeveloped countries. It can also be used as a means to maintain a dialogue and provide better appreciation of cultures that are very different from ours. The United States has tremendous credibility to engage other countries in science diplomacy because of our leadership in science and technology. Science diplomacy helped to maintain contact between this country and the Soviet Union during the Cold War years. AAAS has an important program focused on science diplomacy (http://diplomacy.aaas.org/), which not only engages scientists from other countries with our scientists, but also encourages studies on how the process of engagement can be improved and made more effective.

Although I consult worldwide, I focus on the Pacific region because of my own ethnic background, connections, and interest in the region. Most of the region, except for Japan, is demographically youthful. The people in Asian countries tend to have a strong work ethic and be very energetic; they have a history of respect for the intellect; and finally, many of their governments are willing to invest in education and research because they believe that science and technology are essential to future progress and national success.

However, there are tensions across the Pacific. China is experiencing explosive modernization and economic growth. Along with other Asian countries, most notably Singapore, it is attracting the world's scientific work force by offering prestigious positions, well-stocked laboratories, and solid financial support; we are losing jobs by outsourcing them to Asian countries. All this, in addition to our innate distrust of authoritarian regimes (especially in light of China's increasing investments in the military), makes the American public concerned that the United States is losing its edge as a global leader in research and scientific innovation.

Rather than giving in to despondency or competing on military terms, we should seriously assess our own national capabilities and assure that they remain strong. I can emphasize that, according to the International Monetary Fund, we still support more research than any other country (27, 28) (Fig. 4).

David Brooks editorialized recently about advantages that we as nation still command (29, 30). He postulates that success in an information age depends on being a crossroads nation, a “center of global networks” that can “nurture the right kinds of networks.” He states that we are already a nation that exemplifies a crossroads nation by the resources that we have. He points out that the United States is where many of the best of the world's young wish to be educated and where many want to live and work. We have many of the world's great universities. He believes that we provide the best environment for innovation and creativity based on meritocracy and equality of opportunity. There are laws that protect the products of creativity. We have cities that are hubs within vibrant networks. The hubs are creative centers where people from all over the world gather for stimulation and collaboration.

I would add several other U.S. resources. Our culture encourages risk-taking. We accept failure as a learning experience rather than something shameful. And, last, we have a sense of humor, perspective, and optimism. Together, these attributes make the United States unique in the world. We should ensure that all these resources are maintained. Continued investment in our educational and scientific productivity as well as overall infrastructure guarantees that the United States remains the place where energetic, bright minds want to come and work.

Fig. 4.

World of R&D in 2010. Size of circle reflects the relative amount of annual R&D spending by the country noted. [Reproduced by permission of R&D Magazine (28)]

In this new environment of being a crossroads nation, science diplomacy becomes even more important. It will bring nations into a common scientific effort of solving large, complex global problems, such as clean air, clean water, sustainable energy sources, and security. It will help develop common codes of conduct, not only for science, but also for that of a civil society. Science diplomacy should promote peaceful uses for advances in technology and extend the world's efforts to empower women, provide equitable access to economic opportunities, and eradicate poverty and diseases. To be successful, however, we need to avoid arrogance and western-centric views, and behave as true partners in advancing international science as well as the welfare of all its citizens.

Education

Another passion of mine is improving our teaching of science, technology, engineering, and math (STEM). This is natural because as scientists we are entrusted to be the discoverers, guardians, and transmitters of knowledge. AAAS, as well as the National Academy of Sciences, NSF, and many other institutions, have worked hard to promote STEM education for grades K through 12 over the past 25 years.

Much of the success obtained in this area depends on good teachers (Fig. 5). Although I have just mentioned our excellent universities, we do a poor job of attracting and selecting the best of our young to enter the teaching profession, particularly those who want to teach in STEM fields (31, 32). Also, there needs to be professional development long after graduation, as well as support and mentoring. I urge every university with a school of education to make teaching an attractive and challenging profession, and develop in-house programs to support students to become effective and memorable teachers throughout their professional lives.

In addition, the teaching of science and technology at the undergraduate level is undergoing change. Because of the enormity of technical advances that affect our everyday lives, all Americans need to understand science and technology. Moreover, for the budding young professional scientist, an appreciation of the interdependence of different areas of science is essential for future success. As college may be the last formal science experience for many Americans, we as educators must learn how to teach science subjects in a more integrated fashion rather than forcing undergraduate nonscience majors to fulfill their one or two science requirements by choosing among disciplinary silos. Encouraging improvements in undergraduate STEM education is occurring at many colleges and research universities due to grants made by the Howard Hughes Medical Institute and the NSF.

Fig. 5.

The author with a teacher, Florence L. Newbold, who had a profound effect on her life.

CREDIT: THE HUANG FAMILY

We also need to develop diverse teaching methods (33). An excellent example is provided by a presentation given by Graham Walker at the last annual AAAS meeting (34). At the Massachusetts Institute of Technology, rather than just using technology to drill students, he has created several innovative computer programs where students can learn new subjects by creating a hypothesis, devising experiments to test the hypothesis, and altering the parameters themselves. These experiments are then carried out on computers by students who interpret their results in light of their previous hypothesis. The programs are organized in such a way that students can explore particular areas in depth. Such programs are especially useful for challenging individual students when the class size is large. Another example is the Joint Science Department of Claremont McKenna, Pitzer, and Scripps Colleges, where faculty from three different science disciplines (biology, chemistry, and physics) teach together and use computerized graphics to test quantitative assumptions about complex environmental interactions.

Diversity in Science

To attract and retain women and minorities in the sciences, we need to understand the diverse motivations that make students commit to a life in science. Carnegie Mellon's School of Computer Science is a good example of how to encourage more women to enter the computer science field and to retain them (35). The faculty did widespread outreach to high school students by sending their female students as recruiters. They also initiated a summer course in Pittsburgh for teachers of high school computer classes nationwide to attend. The Dean had to convince the faculty that certain prerequisites, like programming, which excluded students from smaller or poorer high schools, were not really necessary for admission. After the first year, those students without prior training could program as well as students who had been exposed to programming during high school. Strong, ongoing social support was provided by recruiting a well-known senior woman computer scientist. Finally, faculty found that the course on algorithms attracted few women students. The faculty initially thought that women dropped out or did not take the course because they found it too difficult. But women interviewed reported that they had lost interest because they did not see relevant applications for designing complicated algorithms. So it was decided that the first session of the course would be devoted to how algorithms could be used to help social causes. Once this began, the retention rate for women more than tripled. Now all the professors at the college spend the first class sessions introducing their courses by discussing the relevance of the material that will be presented. The take home lesson is that learning what motivates young people from different backgrounds and then using that knowledge to attract students to science and retain them are extremely important. Also, there is no need to dumb down the substance that is taught; how it is taught is what is important.

Attracting diverse populations into science and retaining them will not be useful to society if they cannot reach their full potential and do not have access to all the opportunities that exist. In 1974, a few women microbiologists and I were the first to bring attention to the plight of women scientists. We designed a careful survey and then analyzed the data with the help of sociologists and statisticians (36). It showed that there was a salary disparity as great as 32% between female and male scientists, with women earning less. Women were also promoted more slowly and received less encouragement to pursue advanced degrees and management positions. Happily, there have been tremendous changes for women scientists in America over the last 40 years. Salary differentials between women and men are smaller, and women are being hired more frequently in a variety of previously male-dominated professions. However, we should not feel complacent, as improvements are still needed. The UN/World Bank gender index released for 2010 placed the United States 84th compared to other countries and showed that in our government we have only 17% female leaders, in contrast to 38 to 45% in Scandinavian and other countries. Although this percentage includes only women in parliament or its equivalent, the data pertain to many professions in the United States, including science and engineering. Aggregate statistical data from the Equal Employment Opportunity Commission for 2009 comparing the proportion of all professionally trained individuals to those who make it to middle- and top-level management positions as well as executive positions show that different minority groups and women in industry face a glass ceiling (37). Compared to white males, women professionals have only a 67% chance of reaching middle to top management and executive positions. Similarly, all minority professionals have a lower chance than all white professionals of reaching these higher levels. Surprisingly, Asian Americans have the lowest chance (54%) of reaching such levels when compared to Blacks (89%) and Hispanics (102%), even though Asian Americans are known for their educational and economic achievements (38). This is true for academia as well as for government. Given that the number of individuals in the pipeline of professionals capable of being at the management or executive positions is disproportionally large for Asian Americans, these statistics are startling. There may be many reasons for this. But the growing numbers of Asian-American scientists and engineers, now 17% of the workforce in the United States (39) (Fig. 6), and our dependence on their contributions will certainly force us to examine those reasons closely and correct this continuing disparity.

Fig. 6.

Scientists and engineers in science and engineering occupations 2006. [From (39)]

At a time when our country needs to maximize all the intellectual power that we have for innovation and to populate attractive hubs of excellence, we are wasting a large part of our population by not recognizing and rewarding those who have the capabilities to make a difference. In addition, we have a richness of diversity, which can add immeasurably to our abilities to innovate across disciplines as well as across cultures. Only the exercise of leadership from the very top of the professions will erase existing disparities and put the prestigious, lucrative positions as well as positions of responsibility within the grasp of women and minorities. The challenge is to all of us to do the following:

  • Develop complete intolerance for the casual discrediting or minimizing of contributions and accomplishments made by women and minorities.

  • Make sure that the bar is not set higher for women and minorities than for white males.

  • Remove any inequity in pay.

  • Promote qualified minorities and women to prestigious, leadership positions in a timely way.

  • Provide committed leadership for accomplishing these goals.

The promise of a steady job coupled with passion for discoveries and the excitement of viewing new data are more than enough reward for most scientists. But there are also challenges and richness in the life of a seeker of knowledge, in encouraging the diversity of colleagues in science, and in promoting those practices in science that translate to institutional or political change. Hopefully, those of you who share my passions will continue to carry on the work.

References and Notes

  1. The Preparation of Elementary School Teachers to Teach Science in California, prepared by the California Council on Science and Technology, January 2010.
  2. U.S. Equal Opportunity Employment Commission, www1.eeoc.gov/eeoc/statistics/employment/jobpat-eeo1/2009/index.cfm#select_label.
  3. National Science Foundation, Division of Science Resources Statistics, 2011. Women, Minorities, and Persons with Disabilities in Science and Engineering: 2011. Special Report NSF 11-309. Arlington, VA; available at www.nsf.gov/statistics/wmpd/.
  4. Acknowledgments: I thank my husband David Baltimore and daughter Lauren for their love and support. I am also grateful to Shirley Malcolm, who over many years has shared information freely with me on education, and to Vaughan Turekian, who introduced me to the term “science diplomacy”.

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