Transit Authority On Cell Biology, Proteomics and Career Decisions
Martin Latterich12539 Montellano Terrace, San Diego, CA 92130, USA, [email protected] Source: Martin Latterich (2002). On Cell Biology, Proteomics and Career Decisions. Traffic 3 (12), 932–935.
As I was growing up, my mother introduced me to Einstein and his philosophical literature at a very young age. I was smitten: 'when I grow up, I want to be a Professor' one could hear me boast. Having mostly grown up by now, and having had the privilege to be a faculty member at the Salk Institute, I did live my childhood dream. However, 2 years ago I apparently abandoned my dream and left my position at one of the most prestigious research institutes in the world to start a career in biotech? What were the reasons for this move? Is life 'on the other side' really that much better? Is there a career choice between the two well-defined paths, or is it possible to have the best of both worlds? Are these career decisions terminal? Many students, postdocs, and the occasional faculty member are faced with making a very difficult decision concerning their future. There is no one-size-fits-all answer, and it depends very much on the individual and his or her circumstances which science career track is 'better'. In the following few paragraphs I will speak from my own experience in both academia and industry, with the hope of inspiring some people to carefully plan their futures and decide for themselves on which side the grass is greener.
Life was simple enough when I was young: I loved science and was thrilled each time I had science class, because I knew I would learn something exciting. Biology was especially fascinating, because it is very tangible, yet the most complex of all sciences. When the time came to decide what to do after school, I knew I wanted to study molecular biology and biochemistry with the hope of eventually becoming a professor. I never considered anything else but the academic track, and although many of my classmates took positions in industry, I was not even tempted. After completing graduate school in the UK, I landed a postdoctoral position in the lab of my scientific mentor Randy Schekman at UC Berkeley. Having been accepted by this renowned scientist was a once-in-a-lifetime opportunity for me, and there was nothing that would and could compete.
In the Schekman lab I not only learned excellent science, but also an appreciation of being in academia. Randy soon became my second idol, ranking right after Einstein. During my Berkeley days, I began to investigate why and how the endoplasmic reticulum (ER) fuses, using a reconstituted system that I developed (1). Surprisingly, this fusion event did not require the universal fusion ATPase Sec18p/NSF, but a novel ATPase: Cdc48p (2). Being able to reconstitute ER membrane fusion in vitro then enabled me to test the biochemical requirements for the fusion process. When the time came to look for positions, it was obvious to me that a faculty position was the logical next step. I had proven by now that I could develop my own project, I was not too worried about grants, and Randy Schekman was exceptionally generous to let me take along most of the projects on which I had been working.
The Salk Institute offered a great opportunity to start my own academic laboratory. I continued research on the homeostasis of the ER, driven only by scientific curiosity about how molecular machineries fuse membranes in a controlled fashion. My talented students and postdocs made great progress towards that goal (3–8). We furthermore discovered Cdc48p associates with more than the ER membrane fusion machinery, and indeed is an essential component of other protein complexes. We suspected that Cdc48p is a module, which serves to unfold or extract proteins from protein complexes, and by doing so catalyzes unrelated biological events. This led to the proposal of the differential adapter hypothesis (7), which in recent years has been corroborated by many different groups (3,9–11).
After a few years I began to realize that I needed a new and complementary approach to push my science to the next level. I was very much impressed by the pioneering work done by Ron Davis, who developed gene chips to study genome-wide transcription. Being a protein-centric biochemist at heart, I began looking for ways to analyze and understand organism-wide protein expression and metabolite profiles. This was right about the time when Ruedi Aebersold first published his work on ICAT (12) and when John Yates pioneered MudPIT (13), both techniques that when brought together could allow the proteome-wide comparisons of cells or tissues. A correlation analysis of differential protein expression patterns, protein modifications, and key metabolites could undoubtedly shine some light on the comprehensive phenotype of disease and ultimately would permit understanding of the most probable mechanism. Such differential analysis is clearly no replacement for hypothesis-driven research, but the global information obtained will allow the researcher to consider all possible mechanisms and to perform a better confirmatory experiment in a significantly shorter time-frame. I had high hopes of applying this technology to identify and study the regulatory networks of membrane fusion and cytokinesis.
Further investigation showed that the price tag of a state-of-the-art proteomics facility was close to US$ 3 million, far out of reach for my research budget. The only way was to take the collaborative route by sending out samples to mass spectrometry laboratories. Having had some hands-on experience with LC-MS/MS and wanting to test some new ideas, I was tempted to take a closer look at an opportunity in industry, where funding for such endeavors seemed available. This was a major decision for me because my academic lab was running well. We published key discoveries and grant money was abundant. In an ideal world, I would have kept my academic lab and simultaneously done a sabbatical in industry to learn new skills. Unfortunately, this proposal was not taken favorably because of perceived conflicts of interest. I had to make a decision: staying in academia with the danger of not being competitive in the long term, or embarking on an adventure in industry where I could learn new ways to apply proteomic technology to my science. The latter choice, however, could present a strong possibility of jeopardizing a return to academia at a later stage.
About the same time, a friend who was Vice President at a local biotech company approached me. Her company was setting up a proteomics department and they were looking for a person to drive this effort. I accepted the position, although the most difficult part of the decision was abandoning my academic research and my people. The only comfort was knowing that my work on organelle homeostasis would continue through a graduate student of mine, who would remain at the Salk. The company proved fun and challenging, the resources abundant, and the colleagues enthusiastic. In record time I was able to create a modern differential proteomics platform, hire some good people to run the effort and get the first data – difficult to have done at this speed in most academic settings. After 1 year, a competing offer from another company lured me away. This time, my goal was to build a protein array platform to quantify differential proteomes. A 'first' for me, because my strengths clearly are in the areas of discovery proteomics, cell biology and molecular mechanisms, namely the application of technology, not necessarily the development of technology itself. The entire experience in this new company has been very rewarding and challenging, because most people with my background do not realize what diligent and coordinated effort it takes to come out with a technology product.
Having experienced the advantages and disadvantages of both worlds, I am in a position to comment on both careers. In industry, scientists work as a team to create and deliver a product. Having a successful product launch can be a rewarding experience, because the product can benefit many. This luxury comes at a price: loss of autonomy and job insecurity. To compensate for the higher risks, scientists in industry draw higher salaries compared to their academic colleagues. Generally people in industry have to be much more project oriented and more focused on meeting the company's goal. Since a company is in the business of making money, the welfare of the company rather than the individual influences the decision-making process. For example, entire research efforts can be shut down overnight because of strategic or economic changes. The best-case scenario will be that people are then reassigned to new projects; the worst-case scenario will be that people are laid off. Scientists previously enjoying freedom in independent academic positions suddenly may be faced with reporting relationships to management executives, who may be less knowledgeable than they are, but yet decide the research program and their daily schedules based on corporate guidelines.
Willingness to work in a team, rather than fierce individualism, is a given in industry. Financially, most companies have an annual budget-allocation process. If the research project is central to the company's business, most budgets are never questioned and are generous by academic standards. This allows the corporate scientist to rapidly develop a new research program, or continue an existing one without much paperwork. A leadership position in industry gives one exposure to the way business is conducted, and how science and business form an integral strategic partnership. If a company is successful in delivering a product to the market, the scientific team will have a sense of ownership and the enjoyment of having created something of immediate value, as well as financial gains.
Some issues facing scientists in industry are related to having limited creative freedom and restricted freedom to explore. While I have not experienced this, friends in other companies comment that they encounter very close supervision at all times and that they are fearful of negative consequences if the expected result is not achieved by a predetermined date. People fresh out of their postdoctoral position sometimes feel they are asked to perform tasks that are more appropriate for a lab aide than a highly qualified scientist with 10 plus years experience in conducting independent research. Most contributions are made as a team, and often people are not individually rewarded for their work. Promotion criteria are not as well defined as in academia, and differ greatly among companies. Some scientists find it hard to abandon a perfectly well-running project because of a change in business strategy. Decisions to cut projects may be nonscientific and based purely on financial or strategic criteria.
Most Ph.D. scientists will have worked in an academic lab and will be familiar with life in academia. Some of the pressures facing young investigators are securing grants and working towards tenure. Competition for academic positions has increased dramatically in the past decade. However, grants are available for good projects, and the granting process is generally objective, but it is also long and tedious. The NIH usually funds mature projects with supporting preliminary data to ensure that the project outcome is successful. As a result, it can be difficult to start new areas of research outside of the already funded. In my opinion, there should be additional broad innovation initiatives that reward a productive scientist with additional funds to invest in new ideas in the complete absence of preliminary data. These incentives could allow scientists to be even more inventive and initiate innovative projects that are too risky to be funded by traditional means.
Most complaints I have encountered from my academic colleagues are related to the granting process, tenure decisions and having the responsibility to secure careers for lab members. A faculty member is expected to be creative and productive, but as long as a person is willing to work hard and can publish solid science, the long-term prospects are great. In academia it is very much up to individuals to shape their own careers, and as long as investigators are excited about their research it is a very rewarding career.
In conclusion, both academia and industry have their highs and lows. Many well-respected scientists, such as Peter Kim, Richard Scheller and Gerry Waters have moved to industry; others, such as David Botstein, Joan Brugge, Frank McCormick and Andrei Lupas, have left industry to return to academia. It really depends on what the scientist values most. Does she or he want the freedom to explore basic science and be creative? Or to be part of a team and ultimately see a product reach the market, but be subject to many restrictions and to the economy? Academic scientists can follow their interests or that of their students. Scientists in industry must adhere to the objective of accomplishing corporate goals, often at the expense of following all leads. Academic training is done individually and emphasizes breadth and depth of training. Industry focuses on efficiency and often assembly-line operations, with individuals or groups being experts at a small subset of techniques.
Having said this, other factors can influence this simple choice and need to be considered. Friends and family can exert major pressure on career decisions, as can economic hardship. Many postdocs are not able to make seminal discoveries because the experimental system did not yield expected discoveries and publications in time. This can severely limit career choices or prolong the postdoctoral research period. The career decision process is further complicated by one fact: the longer you remain in industry, the less marketable you are for making an entry into academia. This especially applies to scientists who enter industry after their Ph.D. There are definite exceptions to the rule, but overall it is much easier to move from academia to industry than the other way around. This is especially true for people who have been out of academia for more than 3 years and who may not have been able to publish during this time or maintain a grant. My final suggestion is for graduate students: It would be prudent to stay in academia until you have finished your postdoctoral training, so as to have more options, and then decide whether you want to pursue basic or applied science. Once you have made a commitment to industry, it will be far more difficult to steer back to a faculty position.
I had the opportunity at a recent scientific meeting to meet a very bright postdoctoral fellow, who happens to be at the crossroads of her career. One of her first questions was why I had left such a great faculty position? The second related question was, which one I liked better: academia or industry? Both questions were easy to answer – I left behind a great academic lab in order to explore a new scientific direction, albeit only through sacrificing what I had achieved already. The second question I answered more diplomatically, saying that it really depends on the individual. However, I do know my personal preference.
Einstein worked as a patent examiner for 2 years before he took an academic appointment. It turned out that during this period he had time to reflect (there were fewer patents then) and he formulated some of his most significant scientific contributions. Having been in industry for 2 years, the time has come to reflect on what to do with my own future. I love science and remain the committed basic scientist I have been all along. There is nothing more thrilling than to wake up in the morning and wondering what exciting discovery your laboratory or friends have made. Having had the opportunity to work in industry has given me a new set of scientific and managerial skills that are valuable and make me a more rounded scientist. If I had the choice of choosing the perfect career right now, I would seek out another academic faculty position and apply my new 'toolkit' of skills to start a laboratory for basic cell biology research. I would engage in projects that relate to human disease and that build upon my previous research at the Salk Institute. For my research to flourish, the academic institution must have a proteomics core to support my work. This would ensure that I remain productive for many years to come and would be able to provide many young researchers with modern training and a solid foundation to start their own laboratories. Should my lab make discoveries that are directly applicable, I would start up a company with the concept and take up a role as scientific founder to provide expert consulting, but without direct involvement in its operational and product-to-market activities. Most universities today are supportive of such endeavors and allow the professor to spend 10–20% of his or her time on consulting activity. This way one can have the best of both worlds – basic research lab to understand exciting and important biological phenomena, as well as an outlet to commercialize ideas and eventually benefit mankind by finding a new way to treat disease.
I am grateful to my collaborators, postdocs, graduate students and technicians for doing great science and for making my life exciting and fun, my colleagues in academia and industry for endless stimulating discussions, and especially Randy Schekman for being a terrific mentor over the years. I am greatly indebted to the anonymous graduate students, postdocs and academic colleagues who have read this manuscript and for their expert suggestions and comments.
1. Latterich M, Schekman R. The karyogamy gene KAR2 and novel proteins are required for ER-membrane fusion. Cell 1994;78: 87–98.
2. Latterich M, Frohlich KU, Schekman R. Membrane fusion and the cell cycle: Cdc48p participates in the fusion of ER membranes. Cell 1995;82: 885–893.
3. Hitchcock AL, Krebber H, Frietze S, Lin A, Latterich M, Silver PA. The conserved npl4 protein complex mediates proteasome-dependent membrane-bound transcription factor activation. Mol Biol Cell 2001;12: 3226–3241.
4. Lin A, Patel S, Latterich M. Regulation of organelle membrane fusion by Pkc1p. Traffic 2001;2: 698–704.
5. Patel SK, Indig FE, Olivieri N, Levine ND, Latterich M. Organelle membrane fusion: a novel function for the syntaxin homolog Ufe1p in ER membrane fusion. Cell 1998;92: 611–620.
6. Rouiller I, Butel VM, Latterich M, Milligan RA, Wilson-Kubalek EM. A major conformational change in p97 AAA ATPase upon ATP binding. Mol Cell 2000;6: 1485–1490.
7. Patel S, Latterich M. The AAA team: related ATPases with diverse functions. Trends Cell Biol 1998;8: 65–71.
8. Brizzio V, Khalfan W, Huddler D, Beh CT, Andersen SS, Latterich M, Rose MD. Genetic interactions between KAR7/SEC71, KAR8/JEM1, KAR5, and KAR2 during nuclear fusion in Saccharomyces cerevisiae. Mol Biol Cell 1999;10: 609–626.
9. Hetzer M, Meyer HH, Walther TC, Bilbao-Cortes D, Warren G, Mattaj IW. Distinct AAA-ATPase p97 complexes function in discrete steps of nuclear assembly. Nat Cell Biol 2001;3: 1086–1091.
10. Meyer HH, Shorter JG, Seemann J, Pappin D, Warren G. A complex of mammalian ufd1 and npl4 links the AAA-ATPase, p97, to ubiquitin and nuclear transport pathways. EMBO J 2000;19: 2181–2192.
11. Ye Y, Meyer HH, Rapoport TA. The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature 2001;414: 652–656.
12. Gygi SP, Rist B, Gerber SA, Turecek F, Gelb MH, Aebersold R. Quantitative analysis of complex protein mixtures using isotope-coded affinity tags. Nat Biotechnol 1999;17: 994–999.
13. Washburn MP, Wolters D, Yates JR, 3rd. Large-scale analysis of the yeast proteome by multidimensional protein identification technology. Nat Biotechnol 2001;19: 242–247.
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