The future of science – it’s weird but it works!!
This is my English translation of the essay I wrote for Real Scientists DE.
Our globe is highly connected nowadays. Problems are becoming more and more complex. Challenges are hard to tackle. Relationships are complicated. Our everyday life is highly dynamic. All these aspects also apply to the modern life sciences. Technologies are rapidly evolving. Innovation creates new scientific disciplines, which have never existed before. During the last decades of the previous century it was still sufficient for academic success to characterize a single gene in a model system. Since the breakthrough in the Human Genome Project in 2001, the focus shifted to the systematic study of the complex interplay between all genes of an organism. These new approaches facilitated the development of new sequencing methods as well as the establishment of computational routines for data analysis.
Recent findings in the field of cancer biology indicate that carcinogenesis is a sophisticated process, which cannot be addressed appropriately by conventional methods. If only a single gene existed that caused cancer, one would just need to identify this individual oncogene to combat the tumour. However, as we learned lately, there is not a single type of cancer but various subtypes. Oncogenes do not act in isolation, but they are part of a network and interact with other heritable factors. Besides hyperactive oncogenes, defects in tumour suppressor genes can also contribute to carcinogenesis. It is the dynamic interaction between numbers of genetic elements that causes transformation of healthy cells. Not only protein-coding sequences are relevant in this respect. In fact, the “non-coding” DNA constitutes 98% of our genome and as such contributes to the regulatory complexity of the human DNA. More than 3 billion nucleotides are never translated into proteins. Their sequences plus the information on the DNA of the approx. 20,000 protein-coding genes is not necessarily sufficient to determine a cell as healthy or malignant. We have to bear in mind that all of the 37 trillion cells of our body share the same genome. Chances are slim that mutations accumulate in individual somatic cells and their progeny to make up a significant tumour mass since cellular repair programs exist to prevent this scenario from happening. Errors can also occur beyond DNA replication such as during transcription or translation when proteins are made, and when they are activated, shut off or recycled. The molecular machineries in our cells are highly interconnected, and they act in a dynamic manner. The activity of enzymes can be switch between the on and the off state within seconds by phosphorylation or de-phosphorylation. Other protein modifications occur on different time scales. The spatial arrangement of DNA and proteins in the cell nucleus depends, among other aspects, on the acetylation pattern of histone complexes, which wind up the DNA. Only if the correct chemical group is attached to the right histone residue, DNA can be unwound and be transcribed to execute the genetic program required to maintain cell type-specific functions. But changing the acetylation pattern of histones, subsequently unwinding the DNA, and transcribing and translating it into proteins needs time. In sum, these processes can take up to several hours. Phosphorylation of enzymes and transcription factors in response to a growth factor stimulus occurs rapidly but the subsequent initiation of cell growth can be a slow process since it involves the production of many different proteins.
The ability of a cell to sense growth factor signals depends also on the cellular microenvironment. Cells in the proximity can take up growth hormones thereby preventing the exposure of other cells to those soluble factors. Neighbouring cells can directly interact and alter intracellular signal transduction by secreted messenger molecules or membrane-anchored ligands and respective receptors.
The numbers and different types of cells within a local niche in the human body depend on the lifestyle of the entire organism. There is accumulating evidence that our genes do only partially determine our fate. Our understanding of how our lifestyle affects human health mechanistically is still in its infancy. Smoking does not only correlate with the incidence rate of lung cancer, there is a causal relationship. Tobacco smoke creates polycyclic aromatic hydrocarbons, which interfere with DNA thereby causing mutations that perturb the fine balance of physiological processes in the cells of our body. Mutations are not restricted to a single gene within an individual cell type. Many positions in the genome can be affected by mutations with severe consequences for the equilibrium state of entire cell populations.
Yet, we are lacking a mechanistic understanding of the processes that trigger the onset of different tumours. While causes of carcinogenesis are still under debate, the fatal consequences are widely accepted: cellular transformation, tumour growth and formation of metastases. To deliver optimal and personalized cancer prevention and treatment programs to the people, more than information on the DNA level are required. The DNA is the blueprint of life, but we have to know how the individual bricks, the proteins, are fitting together. Besides, cellular construction and maintenance are highly dynamical and complex processes, which cannot be understood intuitively by individual scientists on their own. Recently, together with a great team, I could show that cell type-specific protein abundance determines cellular signal transduction and proliferation. We measured by means of mass spectrometry the quantities of more than six thousand different proteins from a single sample. These information were implemented in our established mathematical models to predict donor-specific drug combinations to prevent blood cells from growth factor-induced proliferation. The model-based predictions were experimentally validated thereby laying the foundation for personalized medicine in the context of blood cancer in the future. Collaboration between scientists from many different disciplines is a precondition for the translation of basic research into the clinics. To combat cancer, we need experts that overcome borders and push the limits of current technological developments. It requires excellent geneticists, but on their own they would be thrown back to the last century. However when teaming up with highly educated biochemists, computer scientists and well-trained physicians, high-throughput technologies can be harnessed and improved further to optimally treat patients in a rational and personalized manner. The cure for cancer is innovative, interdisciplinary research.
Adlung L, Kar S, Wagner M-C, She B, Chakraborty S, Bao J, Lattermann S, Boerries M, Busch H, Wuchter P, Ho AD, Timmer J, Schilling M, Höfer T & Klingmüller U (2017) Protein abundance of AKT and ERK pathway components governs cell type-specific regulation of proliferation. Mol. Syst. Biol. 13: 904