An Interview with Ann and Manuel Varela: Gunter Blobel- Where are the Proteins? And where are they going?

Mar 27, 2020 by

Günter Blobel

Michael F. Shaughnessy –

1) Günter Blobel was born in Waltersdorf, Germany. When exactly was he born, and what do we know about his early life?

Dr. Günter Blobel was an eminent biochemist who earned a Nobel Prize in physiology or medicine in 1999 for his discovery of protein targeting and delivery to their proper cellular locations, a process called protein sorting. Blobel was born on the 21st day of May in 1936, in what is now Niegostawice, Lower Silesia, Germany.

We know that Blobel had seven brothers and sisters, a rather large family. We also know that when he was a child, he enjoyed horse-drawn sleigh rides in the snow to his grandparent’s home for Sunday lunches. Blobel’s father was a veterinarian who greatly influenced Blobel’s entry into medical studies, along with his older brother Hans, who, like his father, also became a doctor of veterinary medicine.

Blobel studied at the University of Kiel, then moved to the University of Tubingen, taking his medical doctorate in 1960. In late 1966, he defended his thesis and earned his Ph.D. from the University of Wisconsin officially in 1967.

2) Sadly, World War II caused much chaos in his early life- can you briefly summarize the trauma he endured?

Blobel experienced several traumatic events as a child during the Second World War. His family was forced to flee from their home during the Russian invasion in January of 1945. Blobel’s family was large, with eight children. During their attempted escape, the Blobel family stayed on the outskirts of Dresden, in Saxony, Germany. While passing through Dresden at the young age of eight, he was awestruck by the spires and magnificent dome of the Frauenkirche, an 18th-century Lutheran church. From his vantage point, however, Blobel was to personally witness the allied bombing and destruction of Dresden in February of 1945. Before its ruin, Dresden had been highly regarded for its splendid Baroque-style architecture. Seeing firsthand the historic fire-bombing of Dresden was the first significant traumatic event he endured. He never forgot it for the rest of his life.

After this conflagration, the Blobel family then managed to escape westward to the beautiful city of Freiberg, Germany. In later years, Blobel was to recall his life as a child in Friedberg was replete with a richness in culture, like classical Baroque music concerts. Blobel recalled in later years how he blissfully attended performances featuring the works of J.S. Bach, F. J. Haydn, and W.A. Mozart in the city’s Gothic cathedral.

During that same time, however, the family also experienced poor living conditions in Friedberg. To make matters worse, the Blobel family was unable to make good their escape from the Russians. They lived in communist-occupied East Germany. Both food and housing were severely limited. Because of their large family, the children had to be separated, living in different locations in order to have living quarters. Communication with anyone in the outside world was virtually non-existent.

For young Blobel, the most traumatic event was the death of his older sister, Ruth Blobel, who at the time was only 19 years old. She was killed while onboard a train in April of 1945, during a bombing raid, and buried along with her fellow travelers in a mass grave near the bombing site, in the town of Schwandorf in Bavaria. Because of the inadequate communications infrastructure that had been brought about because of the war, the family did not learn of Ruth’s death for over three months. Her death had devastated the family, especially their mother, who mourned Ruth for the remainder of her own life.

Life in communist East Germany was unpleasant for the Blobel family. They were considered bourgeois and denied specific educational opportunities afforded to others wishing to attend college. After high school, in 1945, Blobel managed to escape the communist-occupied East Germany because their infamous wall had not been constructed. His journey led to Tübingen, West Germany, where he pursued studies in medicine at their university, and obtained his M.D. degree in 1960.

3) His brother, also a scientist, apparently was a significant help and influence for his success. What do we know in this regard?

Blobel and his brother Hans, the eldest of the siblings, had somewhat similar educational experiences. Both took their doctorates in medicine, Blobel in medicine, and Hans in veterinary medicine. Both brothers also became interested in the pursuit of scientific research, rather than clinical medicine. They had been incredibly fascinated with unsolved biological problems.

Since Hans was older, he had already moved to the U.S., where under the support of a prestigious Fulbright Scholarship, he acquired expertise in microbiology. Hans eventually became a full professor of microbiology at the prestigious University of Wisconsin.

With assistance from Hans, Blobel acquired a fellowship to enter graduate school in 1962. The graduate fellowship permitted Blobel to study either under Dr. Van Rensselaer Potter II, Dr. Ghobind Khorana, whom you’ll recall we wrote about in our book The Inventions and Discoveries of the World’s Most Famous Scientists, or Dr. Geoge Palade, who is covered elsewhere in this book. Blobel chose Potter as his graduate advisor.

In graduate school, Blobel became enchanted with the nature of the biological cell, especially with its structure and function. Just like his passion for the Gothic architecture of the medieval cities of Germany, Blobel was equally passionate about the architecture of the living cell. For his graduate thesis, he managed to isolate the cell’s nucleus from the intact cell, experimentally producing cellular nuclei in high amounts. He also was successful in determining how protein synthesis and movement of RNA and proteins to the cell membrane coordinated their activities. Dr. Blobel took his Ph.D. from the Potter laboratory at the University of Wisconsin in November of 1966. It was unprecedented, but Blobel consequently had both an M.D. and a Ph.D. degree.

The scientific work forever captivated Blobel, and it motivated him to pursue postdoctoral work with the famous George Palade, who in 1977 would go on to become a Nobel Laureate in medicine or physiology.

4) In terms of mentors—apparently, George Palade was a significant factor. How did Palade help with research and, perhaps, more importantly, the conceptualization of research?

The primary scientific feats that Dr. Blobel accomplished in Ph.D. school fascinated him, and he became further interested in knowing how the cell managed to target and deliver its proteins to their proper cellular locations. In particular, Blobel was curious to know how cells sorted their secreted proteins to a tiny cellular organelle called the rough endoplasmic reticulum. Thus, Blobel decided to pursue postdoctoral studies aimed at learning more about these cellular activities. Therefore, he moved to the University of Rochester, where professor Palade’s laboratory was housed. The research lab of Palade was the premier location for individuals interested in studies of the endoplasmic reticulum.

In the Palade lab at New York, Blobel studied protein secretion from the cell. Working with David Sabatini, a cell biologist in the Palade lab, Blobel, and his colleague learned that as a protein is newly made in the endoplasmic reticulum during translation, the nascent proteins were not quickly degraded but rather were protected from cellular degradation. These proteins thus moved into a new secretory pathway, for exit from a cell. They also showed that ribosomes could attach to and detach from the membrane. They were curious whether the proteins in the ribosomes were different depending on whether they were associated with the endoplasmic reticulum.

Later, in 1975, after Blobel had become a full-fledged faculty member at the University of Rochester, he and Sabatini postulated a daring hypothesis, for which they admitted they had little experimental evidence with which to back it up. They proposed the so-called “signal hypothesis.” It was the only explanation they could find. They asserted that proteins that were meant to be delivered to the endoplasmic reticulum harbored a signal sequence in the N-terminal peptide part of the protein.

In later years, Blobel was to relate how influential his experience in Palade’s lab had been. These postdoctoral years were scientifically formative for Blobel. Palade became an outstanding scientific mentor for him, and he consequently flourished as an investigator. Blobel attributes Palade as his source for learning about the scientific method, formulating hypotheses, and creating an experimental design to test the validity of a hypothesis. These attributes were to serve him well when Blobel took the Nobel for his involvement with the discovery of the secretory pathway.

5) The electron microscope–it is almost as if I need say nothing further- but how did it help in his research and work?

The electron microscope was developed by Max Knoll and Ernst Ruska in the early 1930s. While used by physicists and chemists, the biologists quickly took advantage to examine living specimens. Blobel and colleagues used the electron microscope to study the cellular nucleus, which had been purified in large quantities, making it easier to investigate. The core of eukaryotic cells harbors the genomic material in the form of DNA plus associated proteins for replication, transcription, and gene regulation.

In particular, Blobel had had an interest in the membrane of the nucleus and its ability to transport biomolecules to and from the nucleus. The nuclear core, at the center of the living cell, needs somehow to communicate with the surrounding cytoplasm. One method of nuclear communication is the transport of small and large molecules between the nucleus and the rest of the cell.

In 1950, nuclear pores were discovered embedded in the nuclear membrane. These pores were enormous on a molecular level and were thus referred to as nuclear pore complexes. It was these structures that had intrigued Blobel. Using yeast cells in the early 1990s, Blobel employed the electron microscope to examine these nuclear pore complexes. They further discovered that nuclear transport across the membrane used signal sequences to regulate the movement of individual molecules to and from the nucleus.

In modern times, the nuclear pore complex, also known as nucleoporin, is a well-studied molecular apparatus. Its significance in the fields of biochemistry and molecular biology is understood worldwide.

6) Protein processing– why is it essential to the functioning of the human body?

In general, proteins are processed in order to make them functional and to send them to the cellular location where their activities will do the most good for the life of the cell. Thus, one could certainly argue that the protein processing machinery is necessary for survival.

One way to process proteins is to modify them chemically by attaching new types of chemical appendages, such as phosphate, sugar, lipid, or nucleic acid. Another protein processing system involves cleaving pieces off an intact protein in order to activate, or in some cases, inactivate them, depending on the particular protein.

In the context of Blobel’s work, however, protein processing refers to the cleavage of a leader or signal peptide from a newly synthesized protein and subsequent attachment of a larger sugar molecule to it to form a glycosylated protein during the secretory pathway. This processing system primarily involves those proteins that are destined to associate with the rough endoplasmic reticulum, where ribosomes on the inside make proteins. Further, protein processing also helps to distinguish between proteins meant to be secreted, and those intended for insertion into a membrane. The pathway uses the signal peptide cleavage to permit water-soluble proteins to readily pass through the lipid-soluble membrane of the rough endoplasmic reticulum.

Mechanistically speaking, these signal peptides are attached to the growing polypeptide proteins that emerge from the ribosome that is making them inside the rough endoplasmic reticulum organelle. Inside the rough endoplasmic reticulum (lumen), the signal peptide binds to a so-called signal recognition particle (SRP), which then directs the complex to the organelle’s membrane, where the translocon resides and which is connected to TRAM.

The TRAM unit is a translocating chain-associating membrane protein, which sees a stop-transfer sequence and eventually terminates the protein transfer process. The signal peptide (still attached to the nascent protein) translocates through the translocon and emerges through to the other side of the rough endoplasmic reticulum membrane and occupies the cytoplasm of the cell.

As the rest of the protein emerges through the translocon, the signal peptide peptidase enzyme cleaves the signal peptide, as its job is completed. The protein is now in the cytoplasm, where it can be directed towards its current locations in and around the cellular apparatus.

Figure: Protein secretory and processing machinery

7) Lamins are another aspect of Blobel’s work- but what exactly are they?

The lamins are a family of proteins that function to provide structural support to the eukaryotic nucleus. You’ll recall that the nuclear core is surrounded by a membrane. The integrity of the nucleus needs to be maintained in order for it to accomplish its various functions. Lamins provide this required stability.

Blobel began his investigations of lamin during the early 1980s. His laboratory had first found that his nucleoporin molecules formed complexes with lamins. They then cloned human genes encoding these lamins and found that they were homologous to filament proteins, which are essential for assembly of structural skeletons for cells. In Blobel’s case, the lamins were found to be necessary for the construction of the nuclear frame.

Follow-up investigations were performed in the Blobel laboratory. They set out to purify these lamin proteins, and they succeeded in isolating one of them, called lamin B. Next, they discovered the receptors that bind all three of them, called lamin receptors A, B, and C, from yeast cells. Blobel’s published work in this critical area continued well into the year 2019 and represented one of his last research projects before his death on the 18th day of February in 2018.

8 His Nobel Prize earnings he donated to the city of Dresden—which had endured terrible trauma during World War II. What does this say in retrospect about this great scientist?

As you recall from the answer to your inquiry above, one of Blobel’s major life-changing incidents that he endured was the annihilation of Dresden, which he witnessed firsthand. It was a traumatic catastrophe that he never forgot. Before Dresden’s destruction, he had already developed an interest in architecture, and he was fascinated with the impressive structures of the medieval and Baroque styles, especially those in its famous churches.

When Blobel took the Nobel and received the monetary award, it was said that he donated the entire amount, $960,000, in memory of his deceased sister Ruth, for the restoration of structures that had been destroyed in Dresden.

As you know, Blobel had always been fascinated with the architectures of non-living buildings and living cells. This fascination not only enlightened biochemists and other scientists alike with his studies, but also his philanthropic efforts led to the preservation of equally important historical buildings dedicated to culture, music, and the arts.

For more information about this incredible biochemist, go to:

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