New Beginnings: Getting the Kick I Needed

TURNING points

New beginnings: getting the kick I needed

Kai Simons

I come from the north, from the periphery At that time, in the 1960s, we had few my short visit. I told him about my work in try‑ of Europe — Finland. I studied medicine in international contacts in Helsinki and I had ing to purify Gc protein variants and to find out Helsinki, but actually I wanted to do research difficulty in finding a lab where I could do how these variants differ at the molecular level. and first I tried clinical research. A classical postdoctoral work. I saw a paper by Alexander I recall how Brian not so gently asked me, “Kai, area of Finnish medicine was vitamin B12. Bearn from the Rockefeller University, on do you really think this work is interesting?” Why? Because a large part of the Finnish popu‑ Wilson’s disease, a condition characterized by Deep inside me I knew this work was boring lation was infected with the broad tapeworm, a excessive deposition of copper in all tissues, but I needed this kick from Brian. “Don’t you parasite that colonizes the intestine and needs caused by increased absorption of copper from have another more interesting project that you vitamin B12 for growth. Some people infected the small intestine. Somehow, a serum protein would want to tackle?” Then, I told him about with the tapeworm develop pernicious anae‑ called ceruloplasmin was involved. I joined the Semliki Forest virus membrane and in a mia, which is why vitamin B12 was an area for Bearn’s lab only to find out that they no longer split second he convinced me that this was the medical research. worked on this topic. Instead, serum protein project to pursue. I joined the Minerva Institute of Medical polymorphisms were on the agenda. My encounter with Brian Hartley showed Research as a medical student and my first I continued to expand my knowledge of me that you have to ask ambitious questions project was to measure absorption of vita‑ protein chemistry by purifying and character‑ if you want to get ahead in your research. I min B12 from a patient’s gut. I had to posi‑ izing serum proteins. But most importantly, I had not been taught this before. You also have tion a tube with two inflatable balloons in met a Finnish virologist, Leevi Kääriäinen, who to find an interesting problem to work on. the ileum and repeatedly X‑ray the patient to worked in the neighbouring Sloan-Kettering The choice of system is key to success. Many ensure that I had found the right location. My Institute. He told me about his virus, the Semliki scientists continue to work on the questions patient was an old lady and she was embar‑ Forest virus. I can still vividly remember him that they studied during their predoctoral rassingly grateful to me because I spent so telling me about the virus membrane and how and postdoctoral periods. Real advances can much time with her — little did she realize the virus is enveloped by a piece of the host cell often come from moving sideways and work‑ that it was because of my inability to posi‑ plasma membrane. During this process, only ing in new areas that have not been pursued tion the tube correctly. This was my attempt the virus spike glycoprotein is incorporated and before. Nature is full of fascinating problems, at clinical research. the host proteins are excluded. SDS gel electro‑ accessible to those who have the courage to For my PhD thesis, I instead purified and phoresis, which had recently been developed, think outside the box. When I went back to characterized intrinsic factor, the protein showed that the Semliki Forest virus had only Helsinki, I told my small group that we would secreted in gastric juice required for vitamin two bands: one from the nucleocapsids and now focus on membranes and that we should

B12 absorption. We had to collect 30 l (!) of another from the viral envelope. So, it was the take up the Semliki Forest virus as our experi‑ human gastric juice before we could start the simplest membrane in the world! mental system. We formed a troika with Leevi purification. To collect this volume of gastric Leevi then returned to Helsinki and later, Kääriäinen and with Ossi Renkonen, a lipid juice, my supervisor, Ralph Gräsbeck, hired I too went back. We had both joined the chemist, to work on this problem together. a beautiful nurse who toured the prisons of Haartman Institute, and were working in a In my own group I had the privilege of Helsinki and the line of volunteers steadily new building of the Medical Faculty. I con‑ working with two outstanding graduate stu‑ grew. When she intubated me I suffered laryn‑ tinued my work on serum protein polymor‑ dents: Ari Helenius and Henrik Garoff. With geal spasm (because I have such a sensitive phisms but, the planned collaboration with the Semliki Forest virus in our bags, we three throat) and almost choked to death. Having Leevi on the Semliki Forest virus was slow formed a second troika and soon took off to survived, we successfully purified the protein in getting started. Unexpectedly, a visit to the the recently founded European Molecular for the first time. Laboratory of Molecular Biology (LMB) in Biology Laboratory in Heidelberg. There, we Cambridge led to an important turning point. unravelled how the Semliki Forest virus gets Kai Simons is Research Group Leader and Director I had a Swedish friend who worked with Brian in and out of the cell. Emeritus at the Max-Planck-Institute of Molecular Cell Biology and Genetics, Dresden 0130, Germany. Hartley, a famous protein chemist at the LMB. Competing financial interests e-mail: [email protected] Brian spent quite some time with me during The author declares no competing financial interests.