We Discovered the Garbage Collection Truck of the Body
Dr. Aaron Ciechanover
Technion - Israel Institute of Technology
By the late 30s or 40s, it was established that the body is a chemical laboratory where various complex transformations are taking place incessantly. In the early 50s, it was discovered that proteins are degraded by an organelle called lysosome. The lysosome was thought to degrade proteins that are taken up by the cell from the extracellular environment, as well as the cell’s own proteins, so scientists thought that the problem of protein turnover was solved. Additionally, between the 1950s and the early 1980s, many researchers were busy with the secrets of protein synthesis and the central dogma of biology, which involves the flow of genetic information from DNA to RNA, and then to proteins. Very few were interested in the degradation of proteins.
By the time I became a graduate student with Avram Hershko in the late 1970s, scientists realized that protein degradation is more complex than they initially thought. They learned that proteins that are not necessary anymore, that completed their “job,” or were abnormal (mutated, denatured, misfolded) were selectively degraded. Lysosomes are not equipped with the mechanism to distinguish between normal and abnormal proteins, or between proteins that are still needed and those that have completed their function. Thus, it was concluded that an additional, non-lysosomal system must fulfill this function. Lysosomes are involved mostly in breaking down proteins entering the cells from the outside environment which include signaling proteins, proteins that carry cargo from the outside to the inside of the cell (e.g. lipids, iron) but also proteins that serve as source of nutrients for the cell. The lysosome digests them, and from the released building block builds its own. In contrast, tracellular proteins, the cell’s own proteins, must be broken down by a different machinery.
I was a graduate student working in Avram Hershko’s laboratory when we started searching for this elusive non-lysosomal system. We studied young red blood cells, which do not have lysosomes, but nevertheless degrade their proteins. This was in the late 1970s, when molecular biological tools were not yet available and we used classical, yet extremely elegant biochemical tools to identify the system. We found that a small protein called ubiquitin is attached to other proteins, marking them for destruction at the right time and place. We were able to identify all the principal components of the system, close to 10.
Then, in 2000, with the unraveling of the Human Genome, the complete landscape of the system was discovered – more than 1,000 members that belong all to the big family of the ubiquitin system, which is the largest known family in biology. They are all needed in order to tag specifically the many thousands of substrates the system targets, not only for degradation as we now know, but for many other functions as well. It is a marvelously huge system that is involved in basically all fundamental life processes in plants, and living organisms.
If people ask me what we discovered, I say we discovered the garbage collection truck of the body. It is the ubiquitin system that identifies wrong, useless, misfolded, denatured, or otherwise mutated proteins in the body--harmful proteins, and removes them selectively from the body while sparing all the healthy components we need to stay alive and well. This is directly related to cancer because if something goes wrong with the system and aberrant proteins such as oncogenes (cancer causing proteins) accumulate, disease may result.
But thanks to the work of thousands of researchers worldwide, conducting hundreds of thousands of studies, we now know that the system does much more than remove garbage.
The system also removes healthy functioning proteins that have completed their function and are no longer needed. It directs proteins to different destinations in the cell, activates some proteins, inactivates others, and connects proteins to their partners. It is therefore involved in all fundamental cellular functions, among them DNA damage control, proteins quality control, cell cycle and division, differentiation, and signal transduction.
As a result, and based on our discovery, pharmaceutical companies discovered a way to repair some of these defects that cause the ubiquitin system to allow oncogenes to accumulate. One of these drugs, called Bortezomib or Velcade, is being used successfully to fight a quite common type of blood cancer called multiple myeloma. Until the advent of this drug, patients who suffered from this disease typically died shortly after diagnosis. Now, by taking Velcade, along with another magic drug, a derivative of thalidomide, which also acts via the ubiquitin system, patients are living for many more years with a high quality of life, and many are cured. I can say with pride that we impacted the lives of myriad people worldwide, which is a great source of satisfaction.
We continue to battle cancer by trying to understand additional fundamental mechanisms of disease, which will lead to the discovery of many more useful drugs. Some diseases we will be able to cure. Others we will be able to control so that patients can live a long, high quality life as they do now with diseases such as diabetes and high blood pressure.
I am optimistic that we are going to win this battle. There is not going to be one daywhen we shall wake up to find that the newspapers say cancer is gone forever. Rather, it will be that one type of cancer disease will be defeated, and then another one will be defeated. From one disease we shall learn about the complexity of the other. So, from the brain we shall learn about the pancreas, and from the pancreas about the liver, and the process will be expedited and accelerated.
Eventually, I truly hope, I can almost feel, we are going to live in a cancer-free world.