Proteins. We all known them from the ‘Nutritional Facts’ tables on food packaging materials, but did you know that thousands of different proteins are working together in our bodies to let us live the way we do? I would say that this is quite fascinating, just like that it is quite fascinating that there is still so much we do not know about proteins yet. Obviously, many scientific researchers are working hard trying to better understand protein synthesis (i.e. production), functioning, and degradation (i.e. breakdown). Despite their work, however, it almost seems like that more questions are being raised than being answered.
During my PhD, I had my fair share of protein-related projects, and I dare to say that I learned quite a bit about these wonderful molecules. For example, I know that our DNA contains the genetic code that is needed to make proteins and that the synthesis of every protein starts with the ‘reading’ of DNA. Guess who is doing this DNA reading? Proteins of course.
What specific ‘reading proteins’ do, is translating the very compact ‘DNA language’ that is written in so-called nucleic acids (indeed, the N and the A in the abbreviation DNA), into the more complex ‘protein language’ that is written in so-called amino acids. To illustrate the latter complexity, DNA ‘stories’ are written using only four different nucleic acids, while the story of (human) proteins is written using twenty different amino acids.
I can take this writing analogy one step further since someone (or someones) one day decided to assign each amino acid a single-letter code to simplify the way we write down the amino acid sequence of a protein. A hypothetical protein with the amino acid sequence ‘ILIKEWATER’, for example, would contain the amino acids isoleucine, leucine, isoleucine, lysine, glutamic acid, tryptophan, alanine, threonine, glutamic acid, and arginine. Admittedly, this protein would be so small that I am probably not allowed to call it a protein, as ‘peptide’ would be the appropriate term for ILIKEWATER. You must understand, however, that I sometimes take a shortcut to keep my texts as simple as possible. I am obviously not feeding you with dangerous fake news, so please rest assured. My poetic license is arguably quite harmless and will likely not be considered as a major issue in the eyes of my biology teachers in high school, my chemistry professors at university, and the protein experts who supervised me during my PhD. Again, please rest assured.
Back to proteins. When we write a story in protein language, we can put one of the twenty amino acids on each position. For a protein made of 10 amino acids, like ILIKEWATER, this means that we, in theory, can already make more than 10 trillion (i.e. 20 x 20 x 20 x 20 x 20 x 20 x 20 x 20 x 20 x 20) different combinations. Now take into account that our proteins roughly consist of 100 to 30,000 amino acids. With that information, I guess you would be surprised if I told you that we only have 20,000 different proteins working together in our bodies.
Well to be honest, we have more than that. No single protein (as far as I know) comes in only one form, just like that not every oak tree looks exactly the same. Actually, if you read my PhD thesis than you should now this already. (If you have not done so, please do not bother reading it. Just invite me for a drink, and I will give you a summary of the highlights) What is important to know, is that there are approximately 20,000 ‘stories’ written in our DNA that can be translated into proteins. Based on the needs of our bodies, however, each story can be translated in a different way thereby leading to different forms of the same protein. Just imagine that you are reading my favorite children’s book ‘Where the wild things are’ to your son or daughter when your child is 2 years old and then again when he or she is 5 years old. Obviously, the story remains the same, but the way you tell it to them will be different. You basically tune the story to the needs and capacities of your child, which is comparable to how our reading proteins translate DNA to proteins. At different time-points, the body may need a different form of the same protein, and our reading proteins then act as parents and decide what parts should and what parts should not be translated.
But wait, there is more. Allow me to put forward an example which underlines the astounding complexity of the proteins in our bodies even more. For this example, I would like to zoom in on the protein called ‘epidermal growth factor receptor’, or EGFR in short. This protein is a receptor protein, which means that other proteins can bind to it which will trigger an action. For EGFR, there are many proteins that can bind to it, and this binding can lead to the growth of cells or tissues. This growth is very important for us human beings, so we should be happy that we have EGFR.
It should be noted that EGFR’s action is not always needed, and our body thankfully has the fantastic ability to regulate the activity of EGFR (via proteins of course). But sometimes it happens that EGFR is synthesized in such a way that ‘regulator proteins’ cannot control its action anymore. In such cases, an EGFR variant is produced that cannot be ‘switched off’, which may happen as the result of so-called ‘mutations’. Mutations are DNA alterations (i.e. a change of the story) which can happen for many reasons. For example, mutations occur as a result of long-term exposure to toxic cigarette smoke, but they sometimes also occur just by accident. Indeed, our body works in mysterious ways.
If you read my previous post, you may already know where I am going with this story, but for now please be patient and keep in mind that mutations can be a very good thing. In fact, if our DNA did not get mutated throughout the course of history, we could have never evolved into the awesome homo sapiens that we are today. For EGFR in my story, however, the mutations I referred to in the text above are a very bad thing. That is, when we cannot control a receptor that triggers cell and tissue growth anymore, this will lead to the formation of the life-threatening masses, also known as tumors.
For quite some decades now, it is known that EGFR is one of the many interesting targets for anti-cancer therapy, and already in 1998 the first EGFR blocker was tested in clinical studies. This compound with the catchy name ZD1839 (later called gefitinib) was found to be effective for some cancer types, in particular for one type of lung cancer, namely the so-called ‘non-small-cell lung cancer’, or NSCLC in short. Strangely, it was found that this compound showed surprisingly good responses in female subjects, in subjects of Asian origin, in never-smokers, and in subjects having a specific NSCLC sub-type which is called ‘adenocarcinoma’. These results could not be explained back then and thus triggered researchers to come up with explanations for the varying responses to this drug, as were observed in clinical studies.
Before continuing, it is very important to realize that the above-mentioned observations were made in the same time that researchers managed to unravel the entire human genetic code. DNA was thus a hot topic in those days, and it likely does not come as a surprise that researchers quickly found out why gefitinib worked really good in some subjects by studying the DNA of ‘responders’ and ‘non-responders’.
For these findings, we need to jump to 2004, a year in which three key publications were published: one by Paez, Jänne, Lee, and coworkers (Dana-Farber Cancer Institute; Boston, MA, USA) which appeared online on April 29, one by Lynch, Bell, Sordella, and coworkers (Massachusetts General Hospital and Harvard Medical School; Boston, MA, USA) which appeared online on April 29 as well, and a third one by Pao and coworkers (Memorial Sloan–Kettering Cancer Center, New York, NY, USA) which was released on August 25. All three articles reported on mutations in a specific part of EGFR’s DNA, the so-called exon 19 part, and these mutations were found to be associated with good responses to gefitinib treatment. EGFR exon 19 mutations were, as expected, found more often in never-smoking NSCLC patients, and these findings actually represent an important starting point of personalized therapy in lung cancer.
Gefitinib (together with the drug erlotinib which can currently be found on a bathroom shelf at my parent’s place) forms the first generation of targeted treatments for NSCLC patients who have an EGFR mutation in exon 19. There is currently also a second and even a third generation of blockers for this mutated protein available. Therefore, people who start taking these drugs may see that as a sign of “hope/chances/possibilities/activity/…”, as my mother wrote to us in a text message last Sunday. Doctors can decide to switch between drugs when the response to a treatment is insufficient or in case of severe side effects. Here it should, however, be noted that the option to switch between multiple anti-cancer drugs is not at all possible for most cancers.
The availability of different treatment options can offer “hope/chances/possibilities/activity/…”, although people who receive targeted EGFR exon 19 blockers should bear in mind that the effect of these individual drugs is only temporary in most cases. When the DNA of EGFR gets mutated once, it is very well possible that one or more additional mutations will occur in time. The three-dimensional structure of the EGFR protein can consequently change in such a way that a once very effective drug becomes ineffective. Such change, which is often referred to as ‘drug resistance’, is one of the greatest fears for people who take targeted anti-cancer therapies but also for their loved ones. I know, this is quite a heavy piece of information, but I believe that it is important to be 100% honest on this subject…
At this point, my post almost reaches a word count of 1,700, and I still have not worked my way towards the clue that I had in mind when I started typing. I actually wanted to put forward that there are different ways of looking at the pill boxes that are lying around in our houses. In addition, I wanted to zoom in on those people who are important for the success of drug-based therapies but who are actually not part of the drug supply chain thus excluding drug developers, prescribers, suppliers, and users (NB: for those who did not know yet: I wanted to talk about researchers). Also, I wanted to stress the importance of not only funding researchers who set out to find the new cure for disease X or Y, but also those who develop tools that can make this search more efficient or those who aim to use existing drugs more efficiently.
But…… I did not address these topics today.
And…… I leave it as it is for now.
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