Chapter 9: Molecules of Life: A General Education Approach to the Science of Living SystemsBack to table of contents
Brian N. Tse, Jon Clardy, and David R. Liu
The life sciences are devoted to the origins, interrelations, functions, and manipulation of living systems. Over the past several decades, life sciences research has made tremendous gains in scope and depth. The widespread application of this knowledge has led to dramatic changes in the way ordinary people live. We eat foods derived from genetically modified organisms, rely on biotechnology for life-saving diagnostics and medicines, and look to biofuels to sustain-ably power our automobiles. More advanced applications such as personalized medicine and stem cell therapies were once thought to be futuristic, long-term goals, but have recently begun to be realized.
The expanding role of science in society raises many ethical questions. Topics such as stem cell research, the theory of adaptive evolution, human reproductive cloning, genetic manipulation, and the patenting of living systems are hotly debated in public circles. Advancing technology has unprecedented potential to change our lifestyles, with intensifying social controversy. How we will respond to these transformations in many cases remains unclear.
The profound impact of recent scientific advances on society warrants a reevaluation of our educational programs. As part of a liberal education, students should be prepared for meaningful civic participation and taught to think critically about the broader consequences of their lifestyle choices (Report of the Task Force on General Education, 2007). The curriculum should expand students’ perspectives on the modern world and encourage them to reexamine their place within it. The curriculum should also prepare students to respond constructively to the societal changes they are likely to experience in their lifetime. The dynamic nature of these goals requires the regular revision of courses, to reflect modern perspectives and practices.
The ubiquity of science in modern society necessitates stronger basic science requirements for liberal arts curricula. Individuals (acting as voters, consumers, or parents) are faced daily with choices that require a functional level of scientific knowledge. If we wish to empower students to make sound choices (lifestyle and civic), we need to ensure that they have the intellectual wherewithal to think critically about scientific matters. A relevant knowledge set should include a basic scientific vocabulary, a clear understanding of fundamental scientific concepts, and an adequate grasp of the scientific process itself.
Establishing science courses for a broad audience requires careful consideration on the part of educators. The goals of general education are unlike those of departmental programs geared toward science and engineering majors; they do not seek to provide a specific knowledge set with vocational relevance and typically do not serve as prerequisites for more advanced technical courses. Rather, general education courses seek to impart a broad understanding of key concepts, facts, and theories while providing a clearer picture of how these ideas relate to real-world problems of wide concern.
Because most science-affiliated faculty were themselves educated through specialized programs of study, science departments are inclined—perhaps through some combination of familiarity, habit, and convenience—to use existing specialist classes as content sources for general education. The distinctly different goals of general education, however, warrant de novo design of these courses. This approach ensures a fresh perspective on scientific theories, a coherent course syllabus, a uniform difficulty level, and greater relevance to current events. A fresh start also provides the opportunity to apply new pedagogical approaches.
Designing a new general education science course involves meeting several distinct challenges. First, the course must be taught at a level that assumes minimal prior scientific knowledge: the material must be accessible to students of all backgrounds. Though educators might be tempted to include intricate detail, such intensity can overwhelm students and prevent them from assimilating the most salient points. If a class establishes itself as unduly work intensive, it will also discourage many students (particularly those who might stand to benefit most) from taking future iterations of the course.
Second, the syllabus must be designed for an audience that has only a casual interest in scientific matters. Most of the targeted students are non-science majors pursuing careers unrelated to scientific research. In light of this fact, the course should emphasize connections to everyday life by relating the lessons to current events, common experiences, or subjects they are likely to encounter post-college. Relevant topics include (but are not limited to) human behavior, disease, medicine, nutrition, and conflicts relating to education, law, and public policy. Adequate time should be spent on the social consequences and ethical dimensions of developing technologies. Emphasis should also be placed on providing an overall positive science experience, so as to encourage a lifelong interest in scientific issues and technological developments. Because these courses do not serve as prerequisites for more advanced classes, few restrictions need be placed on what can (and cannot) be included in the syllabi.
From a pedagogical standpoint, courses directed at a broader audience will benefit from the abundant use of activity-based learning (Report of the Task Force on General Education, 2007). Hands-on activities (such as debating controversial social issues, manipulating unfamiliar objects, or experiencing phenomena through direct sensory exposure) connect abstract concepts to personal experience, thereby demonstrating scientific principles powerfully and intuitively. Interactivity also increases student engagement, facilitates deeper examination of philosophical and ethical implications, and fosters a more productive relationship between the teaching staff and students. Activities that directly complement and build on concepts presented in the lectures help link ideas to life outside the classroom.
The hands-on exercises should require minimal technical proficiency, and must present no significant risk to students (no dangerous chemicals, for instance). Because many institutions have limited classroom infrastructure devoted to science experiments, the activities should also require minimal advanced equipment or laboratory space. If the class format does not provide for extra laboratory time, the activities should be executable within the span of a single section meeting. Additionally, the corresponding activity handouts should focus on ease of use and refrain from dense, abstract language. Tedious write-ups (pre- and post-lab) should be avoided when possible.
Molecules of Life is a novel science-oriented general education course taught at Harvard University. The course uses the dynamic interplay of small molecules and macromolecules as a theme for explaining the scientific principles underlying life. The lectures connect these principles to concrete problems of wide concern, often framing the scientific concepts within a historical, social, economic, or ethical context.
Molecules of Life was designed to meet the requirements of Harvard’s new general education curriculum; its intended audience is a diverse body of non-science majors from all backgrounds and collegiate years. In this sense, the course is not intended to prepare students for more advanced science courses or to provide them with a specific vocational knowledge set. Rather, its central goal is to teach undergraduates the key concepts, facts, and theories associated with living systems. Through its connections to other disciplines, the course also seeks (in some instances by means of disorientation) to provide students with new perspectives on familiar issues and to prepare them to react constructively to the societal change wrought by science and technology. Lastly, the course seeks to provide students with a positive science-oriented experience. In doing so, it hopes to kindle a lifelong interest in scientific matters.
The syllabus is divided into four major parts, to be taught in sequence: Molecules and the Flow of Information, Molecular Messengers in Humans, Molecular Medicines and Human Diseases, and Molecules in Our Future. These units cover a wide variety of topics, such as heredity, evolution, human disease, sexual development, and aging. The lectures make abundant use of case studies and draw upon recognizable stories or trends. Current events (as highlighted by articles from the popular media) are frequently integrated into the discussions.
The course incorporates a unique section format: section time is divided between a weekly review and an interactive activity. Each activity is specifically designed to illustrate and punctuate the material covered in that week’s lectures. The activity syllabus includes (among other tasks) the hands-on extraction of DNA from strawberries, the phenotyping and genotyping of students’ bitter taster genes (TAS2R38), a debate on the legalization of marijuana, a game theory competition between students, and a demonstration of pheromones using live silkworm moths. These activities underscore the fundamental concepts in a memorable fashion, better engage students in the course material, and encourage deeper ethical contemplation. Consequently, the sections play an indispensable role in the course.
In Fall 2008, Molecules of Life (formally listed as Science of Living Systems 11: Molecules of Life) was taught by two professors who each wrote and delivered half of the lectures. The course also employed a non-tenure-track faculty member known as a course preceptor. The preceptor’s primary responsibilities were to design and facilitate the weekly section activities and to assist the professors in the creation of new lectures. The preceptor also oversaw the daily course logistics, including organizing and instructing the teaching staff, maintaining the course website, creating homework problem sets and keys, and holding review sessions. The teaching staff, comprising the above individuals and six graduate students, met weekly to review the progress of the course, listen to student feedback, and discuss upcoming topics. This meeting typically included training for the weekly section activity.
A total of eighty students enrolled in the course for the Fall 2008 semester: thirty-three seniors, twenty juniors, twenty-five sophomores, and two freshmen. By concentration, fourteen majored in economics, seven in government, six each in history and social studies, five in history & literature, three each in history of science and mathematics, two each in philosophy and sociology, and one each in computer science, East Asian studies, English, environmental science & public policy, music, and psychology. Twenty-six students were listed as “undecided” for their concentration.
Molecules of Life followed a standard liberal arts class configuration: lectures were given twice weekly (Tuesday and Thursday) and lasted ninety minutes. The lectures made use of PowerPoint slides and, on occasion, a blackboard. Sufficient time was set aside from each lecture to answer questions from the audience, as questions were strongly encouraged.
Each student was assigned to a one-hour section group that met weekly. Sections, led by a graduate-level teaching fellow, were designed to supplement the course by providing a more intimate atmosphere for discussions. These groups were capped at a maximum of fifteen students. Section time was generally divided between a weekly lecture review and a complementary interactive activity (except in the weeks preceding an exam, when section time was devoted exclusively to review).
Because the course draws heavily from current events, students were not assigned a textbook. Rather, weekly readings were posted on the class websiteand were drawn from popular media sources (such as The New York Times or The Boston Globe) or from the news sections of scientific journals. Scholarly articles were often posted as optional reading for advanced students seeking enrichment. To serve as a primary resource, the lecture slides were posted online with the professor’s notes, written in descriptive prose. Digital video recordings of each lecture were also linked to the website, enabling online review of the lectures at a later time. Three-dimensional computer renderings of important molecules were provided, along with a glossary of scientific terms, as educational supplements.
The class was graded on the basis of exams (50 percent), a final project (25 percent), homework scores (12.5 percent), and participation in section (12.5 percent). Two in-class exams and one final exam were given; the lower of the two in-class examination scores was dropped. Students were also given a weekly homework assignment based on the current week’s lectures. As a final project, students were assigned a ten-page Scientific American–style term paper on an approved topic of their choosing. Suggested topics were posted on the course website throughout the semester. Students also had the option of submitting their project in an alternative format (this was encouraged for students with artistic backgrounds), so long as it accurately represented the scientific concepts. Some submitted musical scores, science-themed children’s books, and creative writing projects in verse.
The course is divided into four interrelated parts: Molecules and the Flow of Information, Molecular Messengers in Humans, Molecular Medicines and Human Disease, and Molecules in Our Future. The units are designed to be taught in sequence because each unit cumulatively builds on the preceding units.
Part 1: Molecules and the Flow of Information (Lectures 1–8)
L2: Structures of small molecules
L3: Shapes of small molecules
L4: The macromolecules of life and the central dogma
L5: The central dogma and its impact on your life
L6: Evolution as a molecular and human phenomenon
L7: Steroids and sexual development
L8: Steroids, birth control, breast cancer, and sexual behavior
Part 2: Molecular Messengers in Humans (Lectures 9–14)
L9: Thyroid hormones
L10: Oxytocin and vasopressin
L11: Adrenaline and its relatives
L12: Serotonin and SSRIs
L13: Cannabinoids and endocannabinoids
L14: Opioids and endorphins
Hour Exam I
Part 3: Molecular Medicines and Human Diseases (Lectures 15–19)
L15: Diabetes and diabetes therapies
L16: Cellular and molecular origins of cancer
L17: The past, present, and future of cancer therapies
L18: Infectious diseases and their molecular basis
L19: Molecules that fight infectious disease
Part 4: Molecules in Our Future (Lectures 20–23)
L21: Drug discovery and personalized medicine
L22: Stem cells
Hour Exam II
The first unit, Molecules and the Flow of Information, introduces the basic properties of small molecules and macromolecules. An intriguing case study of abnormal sexual development (pseudohermaphroditism) provides a striking theme. The section emphasizes the interrelatedness of molecular structure, shape, and function. Steroids (testosterone, estradiol, and so on) serve as models to introduce the basic concepts behind atomic and molecular theory. The biological flow of information from DNA sequence to protein structure (the central dogma) is introduced within the context of heredity, sexual development, and sexual behavior. A lecture detailing evolution at the molecular level provides a historical framework for living systems. The latter lectures of the unit describe how knowledge of the central dogma has significantly impacted modern life, including personalized diagnostics, genetically modified organisms, and the sequencing of the human genome.
The second unit, Molecular Messengers in Humans, focuses on small molecules as dynamic information carriers within the body, specifically as hormones and neurotransmitters. Lectures are taught using small molecule-specific case studies involving thyroid hormones, oxytocin, vasopressin, adrenaline, cannabinoids, and opioids. Emphasis is placed on small molecule-protein interplay, and how this dynamic relationship modulates cellular function. This section also highlights the link between endogenous small molecule messengers and their exogenous analogs (both natural and manmade). For example, students are taught how the identification of the active ingredient in marijuana, tetrahydrocannabinol, led to the discovery of the endogenous neurotransmitter anandamide, as well as to the development of the cannabinoid receptor antagonist rimonabant.
The third unit, Molecular Medicines and Human Diseases, focuses on a select group of diseases that have significantly impacted the history of mankind. Diseases are chosen to showcase three different molecular mechanisms of illness: parasitic infection (viral and bacterial), regulatory imbalance at the body level (type I and type II diabetes), and uncontrolled proliferation of specific tissues (cancer). The lectures also provide historical and scientific perspectives of the drug development process. Key discussions include the relative importance of lifestyle versus genetics, the emergence of drug resistance, and the controversies surrounding the U.S. Food and Drug Administration’s (FDA) approval of new drugs and therapies.
The fourth and final unit, Molecules in Our Future, addresses the rising importance of biotechnology and molecular medicine in society. The lectures discuss the latest advances in stem cells, aging, pheromones, and personalized medicine by introducing the basic scientific principles behind them. Articles from the popular media are frequently cited to establish a real-world connection. The instructors then extrapolate powerful predictions and possibilities regarding their potential social impact. The ethical quandaries that these emerging fields present to society are discussed at length.
SECTION ACTIVITIES OVERVIEW
An essential component of Harvard’s new general education program is its commitment to improved pedagogy (Report of the Task Force on General Education, 2007). Instructors are strongly encouraged to explore formats that will foster faculty-student interactivity and maximize student engagement.
With this directive in mind, Molecules of Life was designed with a unique vision for its sections. A new section syllabus of hands-on activities and topical debates was designed with the specific intent of capturing the students’ attention. Both formats serve as intuitive learning aids; the hands-on activities provide vivid, interactive demonstrations of lecture topics, while the debates allow students to formulate their own opinions on controversial topics of wide public interest. Notably, each section is specifically designed to complement the corresponding week’s lectures.
Although the hands-on activities are reminiscent of more conventional laboratory exercises used in specialized departmental courses, the practical restraints and distinct intentions produce a very different student experience. Each activity requires almost no procedural expertise, assumes minimal scientific knowledge, and utilizes only safe materials and equipment (no fume hoods, gloves, or goggles are needed). The exercises are easily completed in the allotted section time of one hour. To maximize efficiency and minimize tedium, no lengthy pre-laboratory or post-laboratory write-up is required. Background information is provided in a user-friendly “frequently asked questions” format. The teaching fellows are trained to oversee all procedures and to lead all section discussions as necessary.
The section syllabus consists of twelve total section meetings (roughly one section for every two lectures):
Part 1: Molecules and the Flow of Information (Lectures 1–8)
Wk 1: Debate: Genetic research & proprietary information
Wk 2: Activity: Extraction of DNA from strawberries
Wk 3: Activity: Demonstrating the Central Dogma using PTC taste testing and genotyping
Wk 4: Activity: The tricky task of gender determination
Part 2: Molecular Messengers in Humans (Lectures 9–14)
Wk 5: Activity: The oxytocin trust game: a competition for bonus points
Wk 6: Review: Exam I
Wk 7: Debate: The legalization of marijuana
Part 3: Molecular Medicines and Human Diseases (Lectures 15–19)
Wk 8: Activity: Monitoring blood glucose levels in real time
Wk 9: Debate: The benefits & costs of new cancer therapies
Wk 10: Activity: Visualizing the bacterial menace at hand
Part 4: Molecules in Our Future (Lectures 20–23)
Wk 11: Activity: Pheromone demonstration with live silkworm moths
Wk 12: Review: Exam II
Part 1: Molecules and the Flow of Information
The course begins with a brief discussion of the fundamental attributes of small molecules and macromolecules (L1). This introductory approach familiarizes students with life’s molecular participants and establishes a basic vocabulary. Students are given a course overview and are introduced to the concept of heritable versus dynamic information flow in living systems. The lecture then introduces an extraordinary case study based on a 1974 Science article, “Steroid 5-Alpha-Reductase Deficiency in Man: An Inherited Form of Pseudohermaphroditism” (Imperato-McGinley et al., 1974). This report details the unique emergence of pseudohermaphroditism in a rural village of the Dominican Republic where the male carriers of a certain genetic trait are born with ambiguous external genitalia and consequently are raised as females through childhood (see Figure 1). Once puberty is reached, the subjects develop fully into the male phenotype, which includes the appearance of a fully functional penis. The physiological change is so remarkable that the townspeople have labeled the subjects guevedoces—literally, “penis [or testicles] at twelve.” To provide a more personal perspective, a brief excerpt from Jeffrey Eugenides’ Middlesex (2002), a Pulitzer-winning novel that recounts the fictional life of one such affected person, is assigned as a reading.
Figure 1: The Emergence of Pseudohermaphroditism in a Rural Village of the Dominican Republic
The male carriers of a certain genetic trait are born with ambiguous external genitalia and are consequently raised as females in childhood. Once puberty is reached, the subjects quickly develop into the full male phenotype. This unusual phenomenon serves as a striking theme for the introduction of basic chemical and biological concepts. Source: Peterson, R. E., J. Imperato-McGinley, L. Guerrero, T. Gautier, and E. Sturla. 1977. Male pseudohermaphroditism due to steroid 5-alpha-reductase deficiency. The American Journal of Medicine 62:170–191.
The Dominican Republic case study provides a striking introductory example of the link between small molecules, macromolecules, and biology. Understanding the morphological phenomenon of pseudohermaphroditism requires basic knowledge of molecular structure, heredity, and sexual development in human beings. Using this anatomical abnormality as the context, the course transitions to the next two lectures on small-molecule structure (L2) and three-dimensional shape (L3). Lecture L2 focuses on atomic theory and connectivity. Students are introduced to the basic attributes of physical and biological systems. The lecture traces molecular theory from Berzelius to Dalton, for historical perspective. To maximize accessibility, bonding is simplified to a series of rules for each element (carbon forms four bonds, nitrogen forms three, oxygen forms two, and hydrogen forms one). The lecture emphasizes the idea that a molecule’s “information” is stored within its shape and concludes with a lesson on drawing two-dimensional representations of atoms. An analogy is drawn between the evolution of kanji from pictographs and the evolution of two-dimensional molecular notation from early structural depictions of chemicals (see Figure 2).1
Figure 2: Comparing the Evolution of the Kanji Symbol for “Horse” to the Evolution of Chemical Notation
The third lecture (L3) transitions from drawing two-dimensional representations to visualizing three-dimensional molecules. Students are taught the basic concepts behind isomerism and how ambiguous two-dimensional representations can symbolize multiple three-dimensional shapes. Empirically proving that methane is shaped like a tetrahedron (rather than a square) exemplifies how carefully designed experiments can resolve mysteries. The 3-D shape of molecules is shown to be the consequence of atomic repulsion, as demonstrated with a tied bundle of balloons. The lecture emphasizes the three-dimensional shapes of different bond types (single versus double) and concludes with a discussion of atomic complementarity in the context of ligands. Students are briefly introduced to the concepts of hydrophobicity and hydrogen bonding.
Keeping with the theme of pseudohermaphroditism for lectures L2 and L3, steroids are used as the molecular focal points. Students are taught how small changes in molecular connectivity (such as the preservation of a double bond in the failed synthesis of 5 alpha-dihydrotestosterone from testosterone) can produce significant changes in three-dimensional shape and, by extension, profound changes in cellular function (Imperato-McGinley et al., 1974).
The pseudohermaphrodite case study also introduces students to the theme of ethical conflict in science. In the original study, the scientists observed that the causative steroid deficiency also reduces prostate growth and delays the emergence of male pattern baldness. Their observations ultimately led to the development of profitable drugs for the treatment of enlarged prostates and baldness. However, the impoverished subjects of the original study likely did not benefit financially from this commercial application.
In situations such as this, whether or not pharmaceutical companies have a moral obligation to share their profits with their research subjects is debatable. To allow students to engage in meaningful dialogue, the first week’s section activity (Wk 1) is designed as a debate on proprietary genetic information. In this exercise, students are presented with a series of hypothetical health conditions, each comparable to those seen in the pseudohermaphrodite case study. Students are then presented with a series of offers to participate as research subjects in a genetic study and must decide whether they would be comfortable participating given the benefits and drawbacks of each offer. As a whole,this exercise demonstrates to students the difficult ethical situations that can emerge as a consequence of advancing science.
Once the basics of molecular structure have been established, the course introduces the flow of heritable information through the central dogma. The specific goal is to teach students how genetic mutations can dramatically change a person’s physiology, as illustrated by the pseudohermaphrodite case study. Lecture 4 (L4) introduces two key macromolecule families, nucleic acids and proteins, and emphasizes how the order of building blocks dictates a macromolecule’s properties. Students are taught that a protein’s amino acid sequence determines its shape, which in turn determines its function (see Figure 3). As a striking example, test tube samples of jellyfish green fluorescent protein (Tsien, 1998) are distributed in class under fluorescent lighting. A survey of the early experiments in genetics provides excellent examples of scientific reasoning and introduces students to Mendelian inheritance.
Figure 3: Introducing Students to the Relationship between Structure and Function in Proteins
For individuals who have had limited exposure to laboratory work, the concept of DNA is often abstract. Though most people are aware of its central importance to genetics, few recognize that it is a tangible chemical that can be seen, touched, and even physically manipulated given adequate quantities. Hence, to “demystify” DNA, students are given the opportunity to extract the DNA from a strawberry (Wk 2). The extraction itself requires no harmful chemicals (it uses only rubbing alcohol, soap, salt, and water) and allows students to collect visible quantities of DNA from a familiar food item. Students are then able to manipulate the DNA with their bare hands, which allows them to make the connection that DNA is, after all, a physical reality contained in all cells.
The next lecture (L5) connects structure to information flow by detailing how nucleic acids physically encode heritable information, culminating in translation via the genetic code. A survey of the key experiments leading up to the central dogma is given, including simplified descriptions of the seminal work performed by Avery, MacLoed, and McCarthy (identification of the transforming principle), Chargaff, Franklin, Watson, and Crick (the structure of DNA), Brenner (RNA as an information intermediary), and Nirenberg and Khorana (decoding the genetic code itself). To establish everyday relevance, the lecture also details how this knowledge has significantly impacted modern life, particularly through the Human Genome Project. Students are introduced to technologies such as personalized diagnostics and genetically modified organisms. Finally, the mutation behind pseudohermaphroditism is revealed, completing the conceptual link from genetic mutation to steroid deficiency (see Figure 4).
Figure 4: Revealing the Origin of Pseudohermaphroditism through the Central Dogma
Having introduced the flow of heritable information, the course then provides a historical perspective by framing the central dogma within evolution (L6). Adaptive evolution is taught at the molecular level and is shown as the natural consequence of any system exhibiting translation, selection, and amplification with diversification. To overcome any lingering skepticism, an overview of evolution’s supporting evidence is presented (that is, anatomy, the fossil record, and DNA sequencing, all of which support a consistent “tree of life”). Recent examples of “artificial” evolution (the emergence of pathogenic drug resistance and the selection of desired traits in domesticated animals) are also provided. The lecture then describes surprising research that suggests the human race has evolved significantly within the past ten thousand years, citing such examples as the emergence of lactose tolerance in Africa (Tishkoff et al., 2007) and the appearance of different forms of malarial resistance (sickle-cell anemia, thalassemia, and hemoglobin c; Carter & Mendis, 2002).
The third week’s activity (Wk 3) provides a more personal demonstration of the central dogma by showing students the link between their phenotype and genotype. The phenotype utilized is taste sensitivity, a sensory perception. Students are invited (but not required) to test their taste sensitivity for a specific chemical, phenylthiocarbamide (PTC). A person’s capacity to taste PTC at low concentrations is dictated by a certain taster gene, called TAS2R38 (Kim et al., 2005). Two forms of the gene are most prevalent: one is sensitive to PTC; the other is insensitive. Depending on their genetics, most individuals either taste PTC as intensely bitter (a “taster”) or not at all (a “non-taster”). Paper strips containing trace amounts of the compound are commercially available, providing a simple oral assay of phenotype.
To establish genotype, a straightforward PCR/endonuclease digestion assay can be performed (as elegantly described by Merritt et al., 2008) using cell samples taken from students. During the section meeting, students transfer cheek cells to a test tube using a sterile inoculation loop. The section leader collects samples and performs the assays in parallel at a later time. Minimal expertise is needed; the only equipment required is a water bath, a PCR block,and a gel electrophoresis box, all of which are routine equipment for a biology lab. The DNA is extracted from the sample, amplified by PCR, and digested with a restriction enzyme. The resulting DNA samples are then loaded onto an agarose gel for segregation by electrophoresis (see Figure 5).
Figure 5: Using PTC to Link the Phenotype and Genotype of Students
Phenotype was established in class by direct taste testing of PTC-infused paper strips. Genotype of the corresponding taste receptor (TAS2R38) was established with a PCR/digestion assay, using cheek cell samples taken from students. Student number 4 is believed to have a rare form of the TAS2R38 gene that does not digest in this assay (thereby mimicking the common tasting form of the gene) but does not enable PTC taste sensitivity; this finding is consistent with his African heritage.
The results are shown to students the following week, enabling them to see their own DNA as amplified by modern biotechnology. From the gel readout (which is easily explained), one can easily predict if a student is capable of tasting the bitterness of PTC: homozygous dominant tasters will see their amplified DNA band cut into two smaller fragments, and homozygous recessive non-tasters will see their DNA intact as a single band (see Figure 5; Merritt et al., 2008). Heterozygous tasters (individuals bearing one taster gene and one non-taster gene) will have all three bands present in their lane, corresponding to one intact band and two digested fragments. This visual evidence provides students with a direct connection between their genes and their own sensory experience, thereby intuitively demonstrating the central dogma.
The first unit of the course concludes with a pair of lectures that directly link steroids, sexual development, and sexual behavior. The first of the two lectures (L7) begins by recounting the discovery of testosterone, including the intriguing caponization experiments that identified its importance to sexual development. The process of sex determination in human beings is then traced through its biological stages: chromosomal, gonadal, hormonal, morphological, and behavioral. This sequence provides ample opportunity to discuss the biosynthesis of different steroids, the steroid modulation of receptor activity, and the transcriptional activation of genes by nuclear receptors. Specifically, students are introduced to the SRY gene and the TDF protein (a nuclear receptor/transcriptional activator), both of which are key participants in the sex determination pathway. This pathway is then related to pseudohermaphroditism, showcasing how signaling “miscommunications” can result in physiological abnormalities.
The ensuing lecture (L8) focuses on the development of modern birth control. The lecture first introduces how man-made ligands can be used to regulate receptor proteins. Students are taught the differences between agonism, antagonism, and enzyme inhibition. When these principles are applied to the estrus cycle (as governed by estrogen and progesterone), a basic understanding of “the pill” emerges: physiological regulation through well-timed doses of estrogen and progesterone agonists. These concepts are then applied to the development of breast cancer therapeutics in the form of estrogen receptor antagonists (tamoxifen) and aromatase inhibitors (exemestane). The lecture concludes with a discussion of hormones and sexual behavior. The proper steroids are shown to be necessary for both sexual behavior organization and activation (Balthazart et al., 2004). The lecture also touches on the public fiascos that can emerge from incomplete or misunderstood scientific research.
To provide a social context for the process of sex determination, the corresponding week’s section meeting (Wk 4) focuses on the history of gender determination at the Olympics. This practice has its roots in the Cold War,when Western nations suspected Soviet-bloc nations of entering male athletes in female competitions (Simpson et al., 2000). As a consequence, female athletes were required to submit themselves for visual inspection. Eventually, this demeaning practice gave way to more advanced biochemical techniques, such as karyotyping and SRY gene detection. However, such tests have their pragmatic limitations. Many athletes do not fit cleanly into preconceived definitions of gender, thus clouding the issue. The controversy over gender identification in athletic competition continues to this day.
In this activity, students are charged with the task of determining the eligibility of a “female” athlete based on the results of a battery of tests. As the teaching fellow progressively reveals the results of each test (patient history, visual medical inspection, karyotype, SRY gene test, and examination of the androgen receptor gene), students are asked to classify the patient as female or male. After they have been given all the available data and have made their final decision, their choices are compared to the official policy currently used by the International Olympic Committee. A discussion of such policies then follows.
Part 2: Molecular Messengers in Humans
The second unit of the course focuses on the body’s use of small molecules as molecular messengers. Because students have already been introduced to the language of chemistry and the flow of genetic information, the emphasis shifts to teaching principles of biology and chemistry that are more specific. To provide a context for these lessons, the lectures utilize a series of well-known small molecules as focal points.
The first lecture of the series (L9) concentrates on thyroid hormones. Using these molecules as a theme, the lecture introduces the fundamental biochemical principles of acidity, hydrophobicity, hydrogen-bond complementarity, and cell-membrane permeability. The worldwide epidemic of iodine deficiency disorder raises an ethical question: given our scientific awareness of the cause, what is our obligation to assist the world’s poor? Students are also taught the fundamentals of cell signaling, including nuclear-receptor binding, signal modulation by ligand concentration, and transcriptional activation. The lecture then introduces chirality. Samples of (d)-carvone and (l)-carvone, which respectively smell like spearmint and caraway, are passed around. This provides a direct sensory demonstration of the importance of chirality in biology.
The second lecture of the unit (L10) focuses on the hormones oxytocin and vasopressin. This lecture introduces key concepts relating to peptides, including their exponential structural potential and the resulting challenge of their primary structure elucidation. Conformational locking (through disulfide bond formation) is also covered. The lecture then addresses gene duplication and its significance to evolution.
A series of thought-provoking experiments are presented, connecting oxytocin and vasopressin to social interaction. One noteworthy experiment relates bloodstream oxytocin levels to trust between human peers (Kosfeld et al., 2005). In this study, “trust” was measured using a money game. The game requires a subject (the “investor”) to invest a portion of money with a peer (the “trustee”) in order to maximize profit: the greater the trust of the investor (as measured by the quantity of dollars invested), the greater the potential return payout. However, the game includes a counterincentive: the greater the sum invested with the trustee, the greater the risk of losing money because of betrayal by the trustee. The study showed that administration of oxytocin prior to playing the game resulted in higher levels of trust by the investor for the trustee.
The lecture also describes a classic experiment on induced monogamy: the transfer of monogamous behavior from prairie voles (a small, faithful rodent species) to a second, typically promiscuous vole species (Lim et al., 2004). This dramatic behavioral change manifests when the prairie voles’ vasopressin receptor gene (V1aR) is introduced into the ventral forebrain cells of the montane voles through genetic therapy. These experiments present excellent discussion opportunities. In a practical sense, the experiments suggest the possibility of engineering behavior through designer drugs. In a philosophical sense, the experiments invite students to consider the nature of human behavior: are behavioral traits like promiscuity really determined by the presence of a single receptor?
To provide students with a more intimate understanding of the oxytocin trust experiment, the weekly section activity (Wk 5) recapitulates the trust game (Kosfeld et al., 2005) without the administration of oxytocin. Rather than competing for money, students instead compete for homework bonus points.
In the course of the section, each student plays the game twice: once in the role of the investor and once in the role of the trustee. All transactions occur via a worksheet that obscures each player’s name, rendering each action anonymous.
Each student first serves as the investor (see Figure 6). The investor has the option of distributing zero, one, two, or three homework bonus points to his corresponding anonymous trustee. Points that are withheld from the trustee (that is, points that are not distributed) are guaranteed to the investor. The distributed points are multiplied by a factor of three, and one additional point is added. The new total is transferred to the trustee. The worksheets are collected, randomized, and redistributed by the teaching fellow.
Figure 6: Schematic for the Trust Game
Students compete for bonus points, which are counted toward future homework assignments. Students participate in two games, in one as an investor and in one as a trustee. Starting with three bonus points, investors have a choice of investing zero, one, two, or three points with their given trustee. (Points not invested are retained by the investor.) The invested points are then multiplied by three, plus one additional point. The trustee then divides the remaining points between the investor and himself. The back-transfer can range anywhere from zero to all available points. All transactions are anonymous; only the teaching fellow knows the identities.
Each student then acts in the role of trustee for another student. The number of points transferred by the corresponding investor is shown on the worksheet. The trustees choose how to divide the available points between themselves and their investor. (The investor has no recourse to punishment if the points are distributed inequitably.) The teaching fellow then re-collects the worksheets, adds each student’s total from both games (the names are revealed only to the teaching fellow), and shows the results at the end of the section. Though the class results cannot be correlated to oxytocin levels (as was done in the real experiment; Kosfeld et al., 2005), the activity allows students to experience how research programs can measure abstract qualities such as trust. The exercise also provides some entertaining data about the class; for example, in the 2008–2009 class, economics majors were significantly less likely to trust their fellow classmates than were government majors.
The Molecular Messengers in Humans unit continues with a lecture on adrenaline and its analogs (L11). The lecture begins with a brief review of amino acid structure and hormone biosynthesis. Students are then introduced to signal transduction across cell membranes via GPCR activation. The diversity of the adrenergic receptors (a1, b1, etc.) demonstrates to students the necessity (and challenge) of finding selective agonists and antagonists (Liggett et al., 2006). Several adrenaline-based drugs, many of which bind to a different adrenergic receptor, are shown. Of particular note are the beta-blockers, which are frequently used to treat heart disease. The lecture also introduces the neurotransmitters dopamine and noradrenaline, enabling neurotransmitters and hormones to be contrasted. To engage the students’ interest, the lecture also traces the history of dopamine-like recreational drugs from the discovery of ephedrine in ancient China to the invention of ecstasy by Alexander Shulgin. The differing effects of these analogs reemphasize the importance of three-dimensional shape to function. The lecture also stresses the complexity of neurological signaling, citing research revealing significant cross-communication between neural paths.
To provide a more thorough treatment of neurotransmission, the next lecture focuses on the small molecule serotonin (L12). The lesson begins by briefly tracing the historical divide between the neurological theories of electrical (“sparks”) and chemical (“soups”) signal transmission. The lecture then describes an intriguing experiment by Loewi (1957) that confirmed the dependence of nerve signaling on chemicals. As the two theories converged, neurotransmission was eventually shown to travel by both electrical (intracellular) and chemical (intercellular) means. To explain how small molecules can transmit nerve signals, students are introduced to the basic structure of the neuron. The focal point of the lesson is the synapse, including the biosynthesis, inactivation, and recycling of neurotransmitters.
The lecture concludes on a behavioral note. Research is shown indicating that variability in human behavior can be attributed largely to variability within synaptic proteins. Mutations in key macromolecules—such as tryptophan hydroxylase (Zhang et al., 2004), monoamine oxidase (Caspi et al., 2002), catechol o-methyl transferase (Montag et al., 2008), or the serotonin reuptake transporters (Caspi et al., 2003; Lesch et al., 1996)—are shown to correlate strongly with psychological disorders. Similarly, students are shown that human behavior can be modified using small molecules that inhibit or activate these proteins. The development of the antidepressant fluoxetine (Prozac), perhaps the most famous of the selective serotonin reuptake inhibitors, is used as a specific example.
Continuing the theme of neurotransmitters, the next lecture (L13) focuses on cannabinoids, endocannabinoids, and marijuana. After a brief survey of marijuana’s history (tracing its path from a crop in ancient China to an inspiration for a modern television series), the lecture raises the curious point of marijuana’s recreational potency: what is the biologically active small molecule? Answering this question required the development of an animal-based assay. The lecture first traces the work of Roger Adams, whose search for the active ingredient resulted in the testing of marijuana extracts on dogs, prisoners, and the president of a well-known university (Adams, 1942). Though Adams’s work was not finished in his lifetime, his ideas eventually led researchers to the discovery of Δ9-tetrahydrocannabinol (THC). Students are then asked to consider a second question: what is the receptor of this small molecule, and what is its normal function in the body? Students are introduced to the “radioactive bait” experiment, which enabled the discovery of the cannabinoid receptor (CB1), a type of G protein–coupled receptor (GPCR; Matsuda et al., 1990). The third question of the lecture is then raised: what is the endogenous ligand for the CB1 receptor? By modifying the radioactive bait experiment, scientists were able to identify the neurotransmitter anandamide (Devane et al., 1992). This finding, in turn, enabled the discovery of retrograde signaling. The search for cannabinoid-related drugs, including CB1 antagonists (rimonabant; Marsicano et al., 2002) and fatty acid amide hydrolase inhibitors, is discussed, thus linking the lecture to the modern pharmaceutical industry.
To forge a connection between the course’s treatment of marijuana and the outside world, the weekly section activity (Wk 7) is organized as a debate on the legalization of marijuana. The discussion revolves around two short opeds from a recent issue of U.S. News and World Report. The first article, “Too Dangerous Not to Regulate” (Moskos, 2008) argues for the legalization of marijuana, while the second, “End the Demand, End the Supply” (Brown, 2008), argues the contrary. Students are supplied with copies of both articles and are allowed to debate the merits and drawbacks of marijuana legalization. Emphasis is placed on a critical reading of the essays. The ensuing discussion is facilitated by the teaching fellow, who is provided with additional useful information: the official American Medical Association (AMA) position on medicinal marijuana, the list of Drug Enforcement Administration (DEA) drug schedules, and the latest FDA ruling on the medicinal benefits of marijuana. When the course was taught in 2008, this discussion topic was particularly relevant to current events in the state of Massachusetts: the November ballot included a referendum on the decriminalization of smaller quantities of marijuana. (The measure would go on to pass.)
The final lecture of the unit (L14) focuses on opioids and endorphins. The lecture begins by tracing opium addiction from the ancient Sumerians to modern times. It includes a selection from Thomas De Quincy’s personal account of opium addiction, Confessions of an English Opium-Eater. Students are then introduced to the properties of freebases and hydrochloride salts. Because morphine is the most complicated chemical structure hitherto shown in class, molecular models are passed around to showcase morphine’s unique three-dimensional shape. A thorough case study of morphine’s features (see Figure 7) recapitulates the unit’s key lessons: its basic molecular properties, its biosynthesis from amino acids, its chemical derivatization into morphine analogs (heroin, codeine, and so on), and its use as a biochemical probe. As with THC, morphine’s use as a probe enabled the discovery of both endogenous receptors (µ-opioid receptors; Pert & Snyder, 1973) and endogenous ligands (the endorphins and enkephalins; Hughes et al., 1975). A discussion of analgesics and their relationship to the µ-opioid receptors follows.
Figure 7: An Examination of the Unique Structure of Morphine
Studying morphine structure provides an opportunity to review the key chemical concepts of the second unit.
The lecture concludes on a philosophical note. One of the key differences between human beings and their close primate relatives is that human beings exhibit higher expression levels of the prodynorphin gene. (Prodynorphin is a biochemical precursor to the endorphins; see Rockman et al., 2005.) These findings raise the questions: What makes us human? Is a primary factor simply our ability to activate a pleasure gene more easily and intensely than chimpanzees?
Part 3: Molecular Medicines and Human Diseases
The third unit of the course offers a molecular view of human disease and has two central goals: to demonstrate how chemistry enables us to understand the origins of disease and to demonstrate how that knowledge set can be used to develop new treatments and cures. The lectures focus on three human afflictions: diabetes, cancer, and infectious disease. Because of the widespread impact of these diseases, the importance of the lecture topics is easy for students to understand. Undoubtedly, many of them have been affected by these diseases, either directly or indirectly.
The first disease to be addressed in the unit is diabetes (L15). The lecture begins by describing its astonishing worldwide prevalence (an estimated 200 million cases worldwide). A brief historical account of the disease is given, noting descriptions of the disease as far back as 3,500 years ago. The lecture then details early diabetes research, which culminated in the identification of insulin as the critical hormone of blood glucose regulation.
The lecture then focuses on the modern perspective. Students are taught the difference between type I and type II diabetes at a basic physiological level. (Type I results from the inability to produce insulin, type II from decreased insulin sensitivity.) The lecture reviews the risk factors associated with type II diabetes: age, obesity, and genetics. A brief aside introduces the emerging technology of whole-genome analysis. A considerable amount of time is also spent discussing the startling rise of obesity in the American population.
The final segment of the lecture centers on existing molecular therapies for diabetes. The first treatment discussed is synthetic insulin, the standard treatment for type I diabetes. The engineered variants of insulin provide excellent examples of applied genetic engineering (Vajo & Duckworth, 2000). The focus of the lecture then shifts to small molecule treatments for type II diabetes (sulfonylureas and biguanides), highlighting their development and mechanism of action. Finally, to reemphasize the importance of lifestyle choices, the relative efficacies of drugs versus lifestyle adjustment for diabetic therapy are discussed (Ratner, 2006).
Though most students possess some level of familiarity with diabetes, relatively few have had the opportunity to use a modern blood glucose meter. In light of this fact, we give students the opportunity to monitor their own blood glucose levels as a section activity (Wk 8). This activity showcases the latest in portable biotechnology (“a laboratory that fits in your pocket!”), while connecting the students’ knowledge of blood sugar regulation to their own bodies. As a safeguard of student privacy and safety, participation in this activity is voluntary.
Students are provided with commercially available blood glucose meters (Lifescan OneTouch UltraMini meters). Students are instructed how to measure their blood glucose level at the start of section. (To ensure safety, students use disposable lancets and meter strips; the strips require only about one microliter of blood for an accurate reading.) Following the first reading, flavored glucose tablets are distributed for consumption. After approximately thirty minutes (during which time the biochemistry behind the blood glucose meters is explained), students re-measure their blood glucose levels to observe how the levels have changed as a result of their glucose consumption (see Figure 8). Students may also opt to measure their blood glucose at additional time intervals, their schedule permitting. Alternatively, students may opt to eat prior to section and monitor the drop in their blood glucose level during the section.
Figure 8: Monitoring Blood Glucose Levels at Various Time Intervals, Following the Consumption of Glucose Tablets
A commercial glucose meter (OneTouch UltraMini) was used for the measurements.
The next two lectures focus on the class of diseases known collectively as cancer. The first lecture (L16) explains cancer as a molecular and cellular phenomenon by framing it as a combination of cellular function abnormalities: self-sustained growth signaling, insensitivity to anti-growth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and the ability to metastasize (Hanahan & Weinberg, 2000). A basic introduction to the cancer stem cell hypothesis is also given (Reya et al., 2001). The latter half of the lecture focuses on cancer as a genetic disease resulting from the accumulation of harmful mutations within a cell’s genome. A brief mathematical primer on probability and mutation accumulation is provided. To emphasize the importance of lifestyle choices, the primary causes of cancer—viruses, radiation, chemicals, and inherited genes—are reviewed in the context of human behavior. Frequently used terms such as oncogene and carcinogen are formally defined.
The subsequent lecture (L17) approaches cancer treatment at the molecular level. The lecture begins by describing cancer therapies (such as radiation therapy and nonspecific chemotherapy) that rely on the general strategy of damaging all dividing cells in the body. A few chemotherapeutic agents (cisplatin, methotrexate, paclitaxel) are covered in greater detail, including basic descriptions of their biochemical mechanisms (DNA damage, DNA replication inhibition, and damage to cell division machinery, respectively). After discussing the drawbacks of such approaches, the lecture segues to newer therapies based on detailed knowledge of specific cancers. A few case studies are provided: imatinib (Gleevec) as a drug for chronic myelogenous leukemia; gefitinib (Iressa) for the treatment of epidermal growth factor receptor–dependent cancers; and bevacizumab (Avastin) for the treatment of vascular endothelial growth factor–dependent cancers. Finally, the lecture examines two newer theories related to cancer research and treatment: the oncogene addiction model and the cancer stem cell hypothesis (see Figure 9).
Figure 9: A Basic Introduction to Oncogenic Theories, including the Cancer Stem Cell Theory
The lecture demonstrates that the improvements in our knowledge of cancer have enabled the development of more sophisticated cancer therapies. Many of these drugs offer hope to patients who would otherwise have no treatment options. The new therapies, however, come with a drawback: the high cost of their development typically results in a high price for treatment. This reality places the drugs beyond the reach of many patients, often forcing families to make difficult cost-to-benefit calculations. Furthermore, the value of these drugs frequently is unclear; for example, a drug can be shown to reduce tumor size without also showing a statistically significant increase in life expectancy.
The FDA approval of expensive cancer treatments has been a controversial topic. To provide a deeper understanding of the scientific and moral dilemmas faced by the FDA, the section activity (Wk 9) is organized as a simulation of the FDA approval process. Students serve as members of the FDA approval board and are asked to judge whether two fictional therapies should be approved for general use by cancer patients. Students are asked to make their decision based on the following six criteria: efficacy, survival rate, specificity, toxicity, economics, and statistical reliability. The data for the two drugs, while fictionalized, are simplified versions of the data on two real anti-cancer drugs chosen because of their controversial FDA review: bevacizumab (Avastin) and sipuleucel-T (Provenge). Once students complete their debates and submit their choices, the teaching fellow describes the real treatments on which the fictional drugs are based. The FDA’s decision on each drug is revealed along with the published rationale. Students then discuss the merits and drawbacks of the FDA-approval process.
The final two lectures of the unit focus on infectious diseases. The first lecture (L18) begins with a discussion of the worldwide impact of infectious disease (which accounts for roughly one-third of all human deaths). The lecture then examines two massive epidemics that have significantly shaped history: the Black Death and the Spanish influenza. The story of the Black Death is traced from its emergence along the silk trade routes, including its unusual use as a biochemical weapon by the Mongols. After briefly discussing the questionable practices of medieval medicine (an era preceding germ theory), the cause is revealed: a type of bacteria (Yersinia pestis) that is transmitted by fleas. Students then discuss the importance of the Black Death as a catalyst for social and economic change.
The second infectious disease examined in L18 is the Spanish flu, which is believed to have killed between seventy-five and one-hundred million people worldwide. The lecture introduces students to viruses, emphasizing their morphological differences from human cells. The lecture raises two interrelated questions: First, what made the Spanish flu so uniquely deadly? Second, why is the age profile of those killed (ages twenty to forty) so different from that of the common flu? To answer these questions, three viral proteins are introduced: RNA polymerase, neuraminidase, and hemagglutinin. Only once they have learned how these proteins function within the common flu can students understand the unusual lethality of the Spanish flu. The lecture concludes with a look at modern viral research, including the laboratory resurrection of the Spanish flu (Taubenberger et al., 2005). The safety issues and ethical dimensions of this research are briefly discussed.
The final lecture of the unit (L19) focuses on the development of molecules that fight infectious disease. The lecture itself comprises three segments: vaccines, antibiotics and antiviral drugs, and the evolution of drug resistance. The segment on vaccines begins with an account of Jenner’s early research on cowpox and smallpox. To aid in understanding vaccines, students are given a basic primer on the human immune system. The lecture then describes the success of modern vaccines in eradicating two major diseases: smallpox and polio. The ethics of producing the first polio vaccine stocks are discussed. Were the first vaccines worth the killing of more than one hundred thousand rhesus monkeys? A brief discussion on the benefits and shortcomings of vaccines concludes this portion of the lecture.
The lecture then switches to antibiotic and antiviral medications, starting with Paul Ehrlich’s development of arsphenamine (Salvarsan), and details the discovery, development, and mechanistic basis for three antibiotic/antiviral drugs: penicillin, oseltamivir (Tamiflu), and saquinavir (Invirase). The molecular target of each drug is introduced (the bacterial cell wall, neuraminidase, and HIV protease, respectively) so that the specificity of each drug can be understood. The lecture concludes with a discussion of drug resistance, which emerges as an inevitable consequence of evolution (as outlined in L6). The three basic mechanisms of resistance are reviewed (avoiding the drug, removing the drug, and destroying the drug), using real examples from resistant bacterial and viral strains.
For the infectious disease section activity (Wk 10), students culture and visualize bacteria that are growing on their hands and test the effectiveness of both hand sanitizer and an antibiotic. For the visualization, each student is provided with ethanol-based hand sanitizer and a sterile blood agar plate. (The plates are regularly used by pathologists to culture and identify common bacterial strains and can be ordered in bulk.) Students are instructed to streak the surface of the agar plate by gently touching the plate with the fingers of their bare hands. One side of the plate is streaked prior to hand sanitizing, the other after hand sanitizing. Students are also given a strip of filter paper infused with ampicillin to place across the plate. At the end of section, the teaching fellow collects the plates and transfers them to a warm room, where they are left to grow overnight.
After sufficient growing time, the teaching fellow removes the plates and digitally scans them. The images can then be emailed to the students. If executed correctly, students should see a plethora of bacterial colonies growing on the “before” side, relatively few colonies growing on the “after” side, and almost no colonies growing in proximity to the antibiotic-soaked paper strip (see Figure 10). For added interest, some of the bacterial strains can be identified based on the hemolysis pattern the colonies leave in the blood agar. This exercise illustrates the omnipresence of bacteria, and demonstrates the effectiveness of both hand sanitizer and beta-lactam antibiotics, as well as the existence of microorganisms that resist a given antibiotic.
Figure 10: Visualizing Bacteria Using Blood-Agar Plates
Students streak their fingers both before and after the use of an ethanol-based hand sanitizer. The plate is then allowed to grow in a warm room overnight. A paper strip soaked with ampicillin is also provided to demonstrate the inhibitory power of beta-lactam antibiotics.
Part 4: Molecules in Our Future
The last unit focuses on four areas of emerging molecular technology: pheromones, drug discovery and personalized medicine, stem cells, and aging. The goal of the unit is to examine how advances in biotechnology and applied science are likely to affect our lifestyles in the near and distant future. Students are introduced to the fundamental concepts that underlie each topic, and recent advances in each field are surveyed. From here, the likely societal impacts of each technology—notably, the social, economic, and ethical conflicts that arise in each case—can be extrapolated (within reason).
The first lecture in the unit (L20) focuses on pheromones. Pheromones are small molecules produced by an organism for release into the environment in order to communicate with nearby members of the same species. The lecture comprises four sections. The first two describe well-understood examples from the insect world. The third section details how pheromones are used by mice. The last section discusses the latest research on human pheromones.
To prime students’ interest in the link between smell and memory, the lecture begins with a quote from Marcel Proust’s Remembrance of Things Past. An account is given of Jean-Henri Fabri’s serendipitous discovery of moth pheromones, providing the perfect research-model organism. This story raises the question: what is the active molecule? The lecture details Adolf Butenandt’s painstaking work (extraction from approximately five hundred thousand silkworm moths) toward identifying the molecule bombykol (Butenandt, Beckamnn & Hecker, 1961). The lecture then describes a more sophisticated insect pheromone system: the use of homovanillyl alcohol by queen bees to inhibit aversive learning by worker bees (Beggs et al., 2007). A brief allusion to Aldous Huxley’s Brave New World provides some thoughtful perspective.
The lecture then transitions to more complex organisms: mice and human beings. Research on the importance of pheromone sensing in mouse mate selection is highlighted. An intriguing series of videos showing mice that have had their pheromone-sensing organ (the vomeronasal organ or VNO) genetically disabled illustrates how pheromones can dictate sexual behavior (Kimchi, Xu & Dulac, 2007). Suppressing the VNO results in male-like mating behavior in females. This surprising sexual behavior model is contrasted with the hormone-based model examined earlier in the course. Finally, a brief survey of the research on human pheromones is given, including examples such as mate selection by major histocompatibility complex compatibility, the phenomenon of menstrual synchrony (Stern & McClintock, 1998), and the search for human pheromones via PET scanning (Berglund, Lindstrom & Savic, 2006; Savic & Lindstrom, 2008). Of particular interest is the finding that homosexual males have cerebral reception results similar to that of heterosexual females (Savic, Berglund & Lindstrom, 2005). Promising research toward identifying human receptor genes hints that exciting new discoveries will appear within the next decade.
To demonstrate vividly the phenomenon of pheromones, students observe an in-section demonstration of bombykol using live silkworm moths (Wk 11). Because adult moths have a lifespan of three to seven days (after emerging from their cocoons, their sole purpose is to mate; they cannot eat), the raising of the moths must be timed carefully. Large silkworm larvae are ordered from commercial sources several weeks in advance of the activity. After raising the silkworms through the final larval stage (using commercially available mulberry leaf chow as the food source), the larvae are left to cocoon in cardboard tubes. The completed silk cocoons are then segregated into plastic cups, where the moths begin to emerge some two to three weeks later. Females are identified through positive identification of a scent gland and are segregated from the males to prevent premature mating.
For the section demonstration, the live male moths are placed on one corner of a wide cardboard tray. In the absence of female moths, the males remain more or less motionless. A female is then introduced to the opposite corner of the tray, where it begins scenting. Upon sensing the pheromone, the males immediately become aroused and start violently stumbling toward the female’s corner. (The moths are a domesticated species that cannot fly.) Students are then shown that dilute synthetic samples of bombykol elicit the same behavioral response from the males.2 Afterward, students are given the opportunity to gently handle the animals. As a whole, the exercise provides students with the chance to witness the real-time use of pheromones by live animals. Repeating the excitation of the males with a synthetic bombykol sample clearly demonstrates the chemical nature of the signal.
As a supplementary activity, students test commercially available colognes that supposedly contain human pheromones. Samples from two different cologne companies (Pheromone Advantage and Alfa Maschio) were obtained for the course. Both companies claim to include active human pheromones in their colognes. At the request of the course instructors, each company sent one “active sample” (with the alleged pheromone) and one “control sample” (lacking the pheromone). Blind aliquots of the four samples were then prepared, with the identities of the samples known only by the preceptor. Volunteers from the class use the cologne over the span of a weekend. At the conclusion of the weekend, the volunteers fill out a short survey gauging whether they felt they had received an unusual amount of social attention that weekend. Though the sample size was small for Fall 2008, the results showed no significant difference between active and control samples. The activity allows students to participate in an entertaining experiment that extends beyond the classroom; it also provides an example of how scientific ideas can be co-opted by the business world, often in questionable ways.
The next lecture in the unit (L21) relates to drug development and personalized medicine. The lecture is broken into three segments: an overview of the drug development process; case studies in toxicity, clinical trials, and intellectual property; and a survey of personalized medicine. After a brief overview of the drug discovery process (a process that requires about $1 billion and ten to fifteen years per drug), students are introduced to the basic considerations of drug design: potency, specificity, bioavailability, biostability, and economics. The chemical features that contribute to potency (shape complementarity, hydrogen-bond alignment, and molecular rigidity) are examined in detail. The lecture then highlights three different modes of drug discovery: serendipity, rational design, and large-scale combinatorial approaches.
The lecture transitions to a series of case studies that highlight the importance of drug specificity and toxicity. The first example is the thalidomide tragedy, in which the sedative thalidomide (or more specifically, an enantiomer of thalidomide) was discovered to be teratogenic. The second example centers on a failed antihypertension drug that was found to induce an unusual but desirable side effect. The result was sildenafil, more popularly known as Viagra. These case studies provide excellent opportunities to discuss such key topics as clinical testing, the FDA approval process, and intellectual property law.
The final segment focuses on personalized medicine. Here, a series of examples illustrates how modern biochemical knowledge has resulted in new medicinal approaches. The first example, warfarin, illustrates how genetic testing enables doctors to set proper dosages for drugs with small therapeutic indices (Rieder et al., 2005). The second example, which focuses on the BRCA1 and BRCA2 genes, shows how genetic testing can help predict a patient’s risk of disease (in this case, breast cancer; Struewing et al., 1997). The last example discusses how genetic testing can help doctors match a patient’s disease to its best therapeutic treatment. For this example, the lecture describes trastuzumab (Herceptin) and its selective potency against human epidermal growth factor receptor 2–dependent cancers (Gown, 2008). A discussion of the outlook of such personalized treatments concludes the lecture.
The third lecture of the unit (L22) focuses on the controversial subject of stem cells. The lecture begins by defining what stem cells are (cells defined by their limitless replicative potential and their able to differentiate into specialized lines) and by reviewing important terminology (totipotent, pluripotent, multi-potent, and unipotent). The lecture then focuses on the sources of stem cells: embryos, somatic cell nuclear transfer, and the reprogramming of differentiated adult cells (Yu et al., 2007). The ethical dilemmas associated with each source are discussed in turn.
Next, the lecture takes a pragmatic turn to discuss the use of stem cells in medicine. The first example presented is hematopoietic stem cell donation, which is used as a treatment for various blood-borne cancers. The second example focuses on a potential therapy, β-cell replacement for type I diabetics (Xu et al., 2008), an idea that was inconceivable only one year earlier. The third example is taken from a news report that appeared just weeks before the lecture was given during the 2008 iteration of the course: the use of stem cells to facilitate the replacement of a body part (see Figure 11; Macchiarini et al., 2008). In this case, cartilaginous stem cells were used to prevent the rejection of a transplanted trachea. The final example details how stem cells might be used to replace a controversial treatment for Parkinson’s disease. The treatment in question requires the transplantation of dopamine-producing neurons from aborted embryos (Rossi & Cattaneo, 2002). With the advent of stem cells, such valuable neurons could be produced in vitro, obviating the need for embryos altogether. A look into the future examines how stem cells might eventually be used to cure “irreversible” neurological disorders such as paralysis (Deshpande et al., 2006). The final segment of the lecture examines the legal, ethical, and philosophical issues surrounding stem cells, including retrieval from embryos, animal reproductive cloning, and human reproductive cloning.
Figure 11: A Demonstrated Use of Stem Cells in the Replacement of a Woman's Damaged Trachea
Cartilaginous stem cells enabled doctors to grow a new layer of patient-compatible cartilage on the transplanted organ. Source: Macchiarini, P., P. Jungebluth, T. Go, M. A. Asnaghi, L. E. Rees, T. A. Cogan, A. Dodson, et al. 2008. Clinical transplantation of a tissue-engineered airway. Lancet 372(9655):2023–2030.
The final lecture of the unit (and of the course) centers on the science of aging (L23). The lecture begins with the Gompertz law of mortality (so named for mathematician Benjamin Gompertz). The concepts of life span and life expectancy are examined, including the historical improvement of life expectancy over time (largely as a consequence of applied scientific knowledge). A philosophical question is raised: if evolution can “perfect” organisms, why do our bodies age at all? In the context of evolution, aging is not a significant selective force, because extrinsic factors (starvation, the elements, predators, and so on) are more significant causes of death (Kirkwood & Austad, 2000). From this key observation, three theories emerge. First, the drop in population with increasing age results in poor selection of age-related genes (selection shadow). Second, beneficial traits are typically selected early, while deleterious traits are selected late (pleiotropic antagonism). Third, metabolic resources are often better used for reproduction than for repair (disposable soma).
The lecture then discusses the latest aging-related research. The first discussion focuses on the nematode Caenorhabditis elegans and how its metabolic pathways are modulated in response to environmental circumstances (Golden & Riddle, 1982; Butcher et al., 2007). A key conclusion from the nematode research is that aging is largely a regulated process, one that perhaps could be manipulated by small molecules. The lecture then documents the shift in approaches to regulating aging, from reversing its effects (“fountain of youth”) to delaying its onset. A survey of age-related research follows: caloric restriction (CR; McCay, Crowell & Maynard, 1935), CR-activated genes, and small molecule mediators of those genes (Howitz et al., 2003). Resveratrol, a component of red wine, is shown to be one such small molecule (Baur et al., 2006). More potent analogs that are in consideration for use as diabetic treatments are discussed (Milne et al., 2007). The last section of the lecture focuses on mianserin and its analogs, small molecules that hold the potential to extend life through a specific serotonin-mediated pathway (Petrascheck, Ye & Buck, 2007). The lecture concludes with an interesting study on caloric restriction, perception, and reality (Libert et al., 2007). Value issues such as quality of life versus quantity of life factor heavily into the ensuing discussion.
As with all Harvard courses, Molecules of Life is evaluated using Harvard’s Cumulative Undergraduate Education system (CUE guide). Overall, in 2008– 2009 the course received a rating of 4.7 (based on a 1 to 5 scale), the second highest rating of any general education class offered over a three-year span (the top-rated course was a ten-student German culture class); this outcome is particularly noteworthy because the average score for a general education class is 3.8 (see Figure 12). Molecules of Life currently ranks as the highest-rated science general education course. When asked if they would recommend the course to their peers, students responded affirmatively; the question rated positively, at 4.8. Representative responses to the question “What would you like to tell future students about this class?” are shown in Figure 13.
Figure 12: Cumulative Undergraduate Education Guide Evaluation for Molecules of Life
Responses based on the Fall 2008 offering of Molecules of Life.
Figure 13: Representative Cumulative Undergraduate Education Guide Responses from Students in Molecules of Life
Responses based on the Fall 2008 offering of Molecules of Life.
The course materials received a rating of 4.8, while the assignments received a rating of 4.6. General education courses receive averages of 4.0 and 3.8 in the same respective categories. Course feedback by the faculty was rated at 4.5, versus a general-education average of 3.8. The course was praised for its well-structured lectures, its organization, its relevance to everyday life, and its balance of difficulty and accessibility. Students also approved of the course materials and website and liked the fact that no textbook was assigned for the course.
The course instructors received ratings of 4.8 and 4.7. The teaching fellows also received very high praise (an average rating of 4.7). The section component of the course received a rating of 4.5, versus a general-education average of 3.9. Students praised the activities as enjoyable and engaging, and many listed the section syllabus as a course strength. The silkworm moth pheromone demonstration was the most frequently cited favorite activity. The strawberry DNA extraction and the blood glucose monitoring session were also frequently listed as enjoyable.
The most significant criticism was lack of depth in topical coverage. Some students desired more scientific detail. Others desired more structured reviews prior to the examinations. Several students felt that the course was not challenging enough.
Because the course is not a requirement for any student, the most concrete indication of its success is perhaps its changing enrollment. Since its 2008– 2009 debut, Science of Living Systems 11 has grown from 80 students to 275, an enrollment increase of 244 percent.
COURSE UPDATES FOR FALL 2009
The Fall 2009 version of the course incorporated several improvements to the syllabus. The second unit of the course (Molecular Messengers in Humans) saw the reorganization of the “Cannabinoids and endocannabinoids” (L13) and “Opiods and endorphins” (L14) lectures into “Opiods and cannabinoids” and “Opiods, alcohol, and addiction.” This change brings the noteworthy topic of alcohol abuse into the course, and provides a framework of addiction for the unit’s recurring theme of illicit drug use.
The second unit also featured a new lecture, “Molecules of food and nutrition,” which approaches food from a chemist’s point of view. Using the ingredients label from a box of cereal as a road map, this lecture addresses such nutritional topics as calories, vitamins, carbohydrates, glycemic index, transfats, and the food pyramid from a molecular perspective, explaining the chemical role of vitamins and how the structure of different types of fat has profound consequences for their health impact. These topics better transition the course to the diabetes lecture (L15) through the subject of obesity.
To improve the syllabus organization, “Evolution as a molecular and human phenomenon” (L3) was moved to the end of the first unit, after small molecule–macromolecule interactions have been addressed. Additionally, “Drugdiscovery and personalized medicine” (L21) was moved to the start of thefinal unit as a better transition from the preceding unit on molecular medicines and human disease. Finally, all lectures were updated and revised based on feedback from the first offering of the course.
The second offering of the course also incorporated new section activities. As an introductory activity, students were provided with “miracle fruit” tablets that temporarily modify one’s taste buds by virtue of a protein called miraculin (Theerasilp et al., 1989). After consuming one tablet, the students are provided with a series of sour foods (such as lemon juice and vinegar), which they will taste as intensely sweet. This activity introduces students to the interplay of small molecules (those we taste as sweet or sour) and proteins (miraculin and taste receptors) through a unique and memorable sensory experience.
The revised syllabus also introduced a field trip to the Harvard Museum of Natural History, providing students the opportunity to view the museum’s exhibit on Darwinian evolution.
Molecules of Life is a novel general education science course that introduces students to the key ideas, facts, and theories underlying living systems by using the dynamic interplay of small molecules and proteins as a theme. The course was purposefully designed for non-science majors, with an emphasis placed on connections to everyday life. The syllabus includes such topics of widespread interest as heredity, evolution, human disease, sexual development, and aging. Considerable course time is spent evaluating the social, ethical, and philosophical dimensions of each topic.
The course also makes use of a novel section syllabus. This syllabus includes several interactive activities, including the extraction of DNA from strawberries, the genotyping and phenotyping of students’ taste receptors, the debating of the legal merits of marijuana, the monitoring of students’ blood sugar levels, and the live demonstration of pheromones using silkworm moths. These activities further engage students and provide them with concrete illustrations of the concepts taught in lecture.
Given the increasing importance of science and technology to modern life, general education science courses should have greater representation within liberal arts curricula. We believe that both the pedagogy and scientific content of Molecules of Life could serve as instructional models for these classes.
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