Ask Stanford Medicine: Dr. Josef Parvizi discusses drug-resistant epilepsy

As part of the Stanford School of Medicine's Ask Stanford Med series, Stanford neurologist Dr. Joseph Parvizi will be responding to questions on the subject of drug resistant epilepsy, and a surgical procedure to help treat the devastating condition. Dr. Parvizi, MD, PhD, is the director of the Stanford Program for Drug-Resistant Epilepsies. Dr. Parvizi will be taking questions both via twitter, or via the School of Medicine's Scope blog. Questions will be collected until Wednesday (June 19) at 5 PM Pacific Time. Both neuroscientists and members of the general public are encouraged to ask a question, and to join the conversation at the Scope blog.

To find out more about the event, or to ask a question or to join the conversation, visit the Scope blog.

To ask a question via Twitter, be sure to include #AskSUMed in your tweet.

The Cruel Irony of Saxitoxin

It was summer of 1997 at Cape Blanc on the western coast of Africa and some two hundred monk seals, nearly two-thirds of the population in the region, lay dead (1, 2). The cause of death was saxitoxin, a highly potent neurotoxin, whose existence is one of Nature’s cruelest ironies. Saxitoxin is a chemical compound, an alkaloid to be precise, that binds to sodium and potassium channels in the brain and muscle (3). This binding obstructs the flow of sodium and potassium ions across the cell membrane, impedes the ability of brain cells and muscle cells to send electrical signals, and can cause death by respiratory failure (3). Certain species of marine invertebrates and fish can accumulate saxitoxin to high levels and then pass it on to their predators. A possible mechanism for this is a difference in the sodium and potassium channels between predators and prey. Interestingly, some species of clam have a mutation in a single amino acid of their sodium channels that makes them resistant to saxitoxin (4), to the detriment of many animals up the food chain, including monk seals and humans. Ecologists estimate that during the fateful summer of 1997, the Cape Blanc monk seals could have been ingesting nearly lethal doses of saxitoxin every day from the fish they consumed (2). And every year, seafood contaminated with saxitoxin kills nearly 300 people and sickens another 1700 (3).

Where does saxitoxin come from? The villains in this story are marine microorganims called dinoflagellates. These microorganisms belong to the kingdom Protista, the dusty attic of taxonomy where biologists place eukaryotic life forms that they really don’t understand. Dinoflagellates are about as closely related to humans as to plants and fungi and incredibly diverse within themselves. About 4000 species have been described, 90% of which live in the world’s oceans and survive either by preying on other single-celled organisms or by doing photosynthesis (5). Most of these species do not produce saxitoxin but do have other curious characteristics, like genomes up to 100 times larger than the human genome, permanently condensed chromosomes in all stages of the life cycle (instead of just during cell division, like in other eukaryotes), and chloroplasts acquired independently of land plants (6). Three genera of dinoflagellates that do produce saxitoxin, Gymnodinium, Pyrodinium, and Alexandrium, get consumed by filter-feeding fish and marine invertebrates that effectively concentrate the poison in their viscera (2, 3). The monk seals at Cape Blanc had the misfortune to be near a bloom of Gymnodinium catenatum and possibly Pyrodinium bahamense (2). Such blooms occur seasonally and may account for other unexplained mass mortalities of marine wildlife (2), though, luckily for humans, many countries have monitoring programs for edible mussels, clams, gastropods, crustaceans, and fish that minimize public health risk (3).

Why do dinoflagellates produce saxitoxin? It is unlikely that they intend to kill marine mammals because the saxitoxin-producing species are photosynthetic (7). Arguably, they would derive no benefit from killing high-level predators in their ecosystems and may even be harmed by an increase in lower-level predators that would result. The large size of dinoflagellate genomes, the difficulty of culturing dinoflagellates in the lab, and their extreme divergence from all organisms with sequenced genomes makes genomic and evolutionary studies of saxitoxin production in dinoflagellates challenging, and information is incomplete (8). The most popular and widely studied hypothesis is that saxitoxin deters the immediate predators of photosynthetic dinoflagellates, such as cocepods and mollusks (3). However, evidence is inconclusive because though saxitoxin production correlates with decreased consumption of dinoflagellates by cocepods, many studies have found no effect of saxitoxin on the survival of mollusks, and other studies found that even dinoflagellate species that do not produce saxitoxin could kill their predators by an as-yet-unidentified mechanism (3). Another hypothesis is that saxitoxin acts as a pheromone and regulates mating and other social behavior in dinoflagellate colonies, though any hypothesis that proposes a non-toxic role for saxitoxin must account for how dinoflagellates that do not produce it perform the same tasks (3). Nonetheless, at present, it is a good bet that dinoflagellates use saxitoxin for their own purposes and that its effect on the brain is a cruel irony.

 Sources

1. The IUCN Red List of Threatened Species. http://www.iucnredlist.org/details/13653/0
2. Reyero M et al (1999). Evidence of Saxitoxin Derivatives as Causative Agents in the 1997 Mass Mortality of Monk Seals in the Cape Blanc Peninsula. Natural Toxins. 7: 311-315. Open access.
3. Cusick KD and GS Sayler (2013). An Overview on the Marine Neurotoxin, Saxitoxin: Genetics, Molecular Targets, Methods of Detection and Ecological Functions. Marine Drugs. 11: 991-1018. Open access.
4. Bricelj VM et al (2005). Sodium channel mutation leading to saxitoxin resistance in clams increases risk of PSP. Nature 434:763-767. Paywall.
5. Dinoflagellates. Smithsonian Museum of Natural History. http://www.mnh.si.edu/highlight/sem/dinoflagellates.html
6. Wisecaver JH and JD Hackett (2013). Dinoflagellate Genome Evolution. Annual review of microbiology. 65: 369-387. Paywall.
7. Algae and Human Affairs edited by CA Lembi and JR Waaland and published in 1989.
8. Hackett JD et al (2013). Evolution of saxitoxin synthesis in cyanobacteria and dinoflagellates. Molecular biology and evolution. 30: 70-78. Open access.

Fix the PhD

Introduction:

From Spring- Fall 2012, I spent some time working as the Neurosciences Program representative to a student advisory board, working on curriculum reform for the Stanford Biosciences umbrella program. While I’m very proud of the work our committee did, particularly with implementing a new set of two week, intensive, hands-on practical minicourses, we ran into some fundamental obstacles when we considered how best to make grad school prepare students for a wide variety of career options. These obstacles existed not in Stanford itself, but in the structure of incentives for graduate schools as a whole. When the NSF put out a call for ideas to improve graduate education, I figured it was worth putting these thoughts into writing. The piece that follows was my submission, and generally outlines my feelings on what a science PhD program ought to look like for the 21^st century.

Broaden the Base of Excellence

In his 2013 State of the Union address, President Obama called for an education policy that increases “focus on science, technology, engineering and math, the skills today’s employers are looking for to fill the jobs that are there right now and will be there in the future.” Though a PhD in science or engineering can—and should—be valuable for any job that involves thinking hard about complex problems and coming up with innovative solutions, PhD programs generally do not train students with these options in mind. A substantial portion of trainees go into careers for which they have little or no training: as of 2011, the National Science Foundation reported that only half of the roughly 50,000 PhD graduates went on to academic postdocs, and that only 15% of the students that graduated five years earlier had become tenure-track faculty. If the underlying goal is innovation and economic growth, then we need to train people to thrive in non-academic-science positions where their scientific skills and expertise can help drive the economy.

PhDs could be starting companies that create jobs, communicating science to lawmakers, teaching the next generation of science students, or developing treatments in biotech and pharmaceuticals. But within the current framework of academic culture and funding incentives, most PhD training programs focus too narrowly on funneling students towards tenure-track academic science. We need to broaden the base of excellence in graduate training, maintaining high standards of quality while expanding the definition to include more careers that benefit from a scientific education.

In the long term, we need to fundamentally shift the culture of graduate school (for both faculty and students), from solely valuing the research that a student produces, to valuing the full range of meaningful contributions that they might choose to make with their training. But such a change cannot happen overnight—institutional factors, implicit biases, and the weight of tradition would not make it easy. In the short term, however, government could catalyze this transition, paving the way for scientific training programs that empower students to use their training for a variety of productive career options. If we change the way incentives are structured for the programs that train our PhDs, if we reward programs for training the best teachers and entrepreneurs alongside quality scientists, more fundamental change can follow.

Many graduate students, particularly those at top institutions, are funded by training grants. Some of these training grants are individual pre-doctoral fellowships, but some are also awarded at the level of a department or graduate program, such as the NSF IGERT program or the NIH T32. With funding for graduate students being a premium resource, the requirements for such grants, particularly institutional training grants, help to shape the structure and culture of training programs. Unfortunately, for many of these grants, the criteria by which a program or a student is judged (number of academic postdocs, number of publications in top journals) are far too narrow. Programs with institutional grants whose graduates later become leaders in industry, policy, or education are, at best, required to explain themselves, and at worst are actively discouraged. The first step in improving graduate education is for such grants to acknowledge that successful training means any career, research included, in which trainees use their skills and expertise to meaningfully contribute to society.

Some funding organizations are already getting on board with this definition. In 2011, the National Institute for General Medical Sciences put out a report calling for a comprehensive overhaul of their training grant criteria for success.  Based on conversations with stakeholders from all parts of the training process, from administrators to faculty to current trainees, the report suggests that the definition of success in scientific training needs to be broader. One version is particularly resonant: “For society, success is having a strong and diverse cadre of creative thinkers and innovative problem solvers.” To this end, the report suggests encouraging recipient programs to provide broad, flexible professional development training, and to encourage a focus on student development, rather than selection of talent alone. But why not go one step further? Funding institutions could actively encourage training programs that support any career path that thoroughly uses the skills and the training that a graduate education provides, and that make partnerships, within their universities and their communities, to offer training in the skills necessary to be competitive in today’s job market.

Institutional training grant applications currently require a description of how the program will provide professional development training to their students, usually focusing on scientific ethics and academic professional development, and individual predoctoral fellowships require statements of broader impacts. Why not also ask these institutions: how are you providing resources to students who want to acquire skills and knowledge outside the lab? How are your students exposed to a broad array of career options? Why not ask trainees on individual fellowships: how will you find the resources you need to succeed in the career of your choosing? Simply asking these kinds of questions incentivizes training institutions to experiment with how best to provide resources and encourage students to seek them out. Some programs might forge partnerships with biotechnology and pharmaceutical companies, or strengthen ties within their university to writing centers, public speaking centers, or career development centers. Others might, for example, set aside two weeks of every term as dedicated professional development time, offering courses in pedagogy, public speaking, interdisciplinary problem solving, or management. In turn, funding organizations can track which interventions get more graduates into jobs that use the skills they have acquired.

The hope, then, is that by changing the structural incentives at the highest level, we might begin the work of updating graduate school for the 21^st century. So that is the dream: a culture of graduate science education that empowers students to be the best in whatever science-related career that they choose, and that arms them with tools for thinking and interacting with others that make them valuable to employers across disciplines. Such a shift, beginning with a change in incentives, is what graduate education needs to train happy, healthy, empowered students who will develop into excellent researchers, leaders, innovators, and entrepreneurs.

Right now, many science PhD programs follow a similar pattern: take courses, perhaps act as a teaching assistant, take an oral and written qualifying exam, and then tackle a mentored project to generate data until you graduate. With those initial hurdles finished, the only measurement of success that a PhD student has—and the only one that has any traction in the current graduation school culture—is progress in the lab. From the qualifying exam to the thesis defense, the most important product of graduate school is the thesis itself, despite the fact that many students who go on to postdocs are not necessarily performing the same techniques or working in the same subfield. But what if students could measure their success not only by the progress of their research, but also by their progress towards the skillset they need for a rewarding career of their choice? What if taking a professional development course on public speaking, teaching, or management felt as valuable as running another experiment?

A PhD program for the 21^st century should focus on the trainee as the primary product of graduate school, and the culture of such a program should encourage a broad base of professional development and successful self-improvement to prepare trainees to meaningfully contribute to society. With such a program, a PhD could signify to any future employer that a graduate has a variety of marketable skills: critical thinking, making and evaluating evidence-based arguments, communicating complex concepts, identifying important problems from a body of background knowledge, and coming up with innovative ways to solve them. The students from such a program would benefit from a clear path to becoming leaders in whatever field they choose, from academic science, to industry, to policy, to teaching.

Admittedly, changing these incentives may require some work to measure and quantify, because the success of a program can no longer be boiled down to statistics about numbers of papers published in high-impact journals and number of students going on to academic postdocs. It will fall to the champions of 21^st-century graduate training to make decisions about what is sufficient breadth of career exposure, sufficient support for professional development, and about which career options are worth investing time and energy into supporting. Simply starting the conversation about re-defining success in graduate science education could be a priceless step towards improving the process, and is essential for building momentum for cultural and institutional change. Funding institutions, by virtue of the power they hold, are in a fantastic position to start these conversations and watch as their effects propagate. By taking those first steps out of the well-trodden path of purely academic definitions of success, funding institutions could become the trailblazers for bringing graduate education in line with the myriad of ways that intelligent, well-educated science trainees can contribute to society.