The next generation of TSC researchers and drugs.
Dr Kacper Rogala has been recently awarded a Fellowship Award from the TSA to work on the project ‘Towards specific mTORC1 inhibitors capable of rescuing TSC loss-of-function’. We caught up with him to find out more about how his career has led to him being involved in TSC research, the work he plans to undertake and what makes him tick outside of the laboratory.
Please describe your academic and career history to date?
I was educated in three wonderful British cities: Edinburgh, London and Oxford, where I studied chemistry of living things, or as we like to call it - biochemistry.
During my undergraduate studies at the University of Edinburgh, I learned basic molecular biology and protein chemistry, whilst exploring certain enzymes involved in cell division. My passion for proteins led me to London, where as a Master’s student with Professor Christopher Kay at University College London and Dr Tracey Barrett at Birkbeck College, I worked on Kaposi's sarcoma-associated herpes virus. This virus is known to enter human cells and to hijack their protein-making machinery to make copies of itself, eventually killing the infected cells. In order to prepare for such an aggressive invasion, it first keeps a low profile and tricks our cells into thinking that everything is okay, and that they should live long and prosper. Knowing your enemy is half the battle, and thus we used advanced paramagnetic resonance tools to study how specific proteins produced by this virus can possibly hijack our cell survival machinery.
Since the completion of my Master's degree, I went on to study for a DPhil at the University of Oxford, where I joined Dr John Vakonakis who was just beginning to build his laboratory. I became his first DPhil student. I was also co-supervised by Professor Charlotte Deane, who encouraged me to expand my computational skills through involvement in many interesting bioinformatics projects. As my main challenge, I chose to study cellular structures called centrioles, which are collectives of hundreds of proteins, and their role is to guide the proper segregation of multiplied DNA material during cell division, or to clean our lungs by sweeping out mucus and dirt. Centrioles are beautiful microscopic structures that look like vertical stacks of many bicycle wheels, with each wheel containing precisely nine spokes. My DPhil work constituted the first report shedding light on how one of the core centriolar proteins, called SAS-5, contributes to building those nine-spoked wheels.
During the last year of my DPhil at Oxford, I became interested in how cells, organs and organisms grow, and how such growth is regulated in health and disease. I devised a long-term project involving biochemistry, structural biology and drug discovery that had a potential to address many baffling questions involving one of the major growth programs of human cells, called mTOR – in the hope that it will provide alternative therapies for patients suffering from dysregulated mTOR function, such as Tuberous Sclerosis Complex (TSC). My proposal successfully gained the confidence of a leading mTOR pioneer, Professor David Sabatini, who invited me to pursue this work in his laboratory. I also initiated a collaboration with Dr Roger Williams, a leading structural biologist in the field of large proteins related to mTOR. Dr Williams offered to act as my co-advisor for this project and provided me with training in advanced electron microscopy techniques, for which I spent a few months in Cambridge, UK, before moving to Boston, USA to work with Prof. Sabatini.
Please could you tell us about the work you will undertake as part of your TSA funded fellowship.
Structural biology and drug discovery. These two disciplines are very closely linked, and together, they can make a real impact for TSC patients. Drug discovery used to be done very differently that it is now. In the past, scientists and physicians did not know the exact details of how diseases worked, and in the hope of finding a cure, they would take the nastiest chemicals they could find and apply them to mutated cells. Chemicals capable of killing those cells were further evaluated for their suitability of treating patients, which, as you can imagine, had variable results. Today, the situation is very different. The large investment in basic biological research over the last 30 years has paid off. We have learned exactly what genetic mutations cause tuberous sclerosis, and precisely what proteins work together to control growth of cells. Now is the time to use that knowledge and the emerging technologies to develop precise medicines that are aimed at rescuing mutations in TSC patients. Medicines that are designed to do a specific job.
A large part of the cellular growth regulation picture belongs to molecular protein machines called TSC and mTOR. While mTOR is the driver of cellular growth, TSC acts as a hand break to regulate activity of mTOR, such that our body doesn’t get too much or too little growth at a specific time and place. TSC protein crippled by genetic mutations in TSC patients is unable to regulate mTOR, and hence the growth in cells impacted by those mutations is completely out of control. We have drugs on the market that can curb the activity of mTOR. However, there is not one class of mTOR in cells, but two, and those drugs hit both of those classes. So, when you take anti-mTOR medicine, such as rapamycin, over long periods of time, then yes, you potentially fix the abnormal growth problems of those cells, but at the same time, you can affect other useful processes in all other cells, such as balance of sugar levels, which are controlled by the other class of mTOR molecules. This, of course, is not ideal, because it increases your risk of developing other disorders, including diabetes.
The large body work from the Sabatini Lab, and from many other labs around the globe, revealed the differences between the two mTOR classes. Having this knowledge, it is now possible to work towards creating medicines that will act only on one mTOR class that is involved in TSC, and not on the other. We want to be able to offer patients something better than rapamycin. A next-generation drug that alleviates all symptoms of TSC, and which they can take daily without having to worry about developing insulin resistance.
What motivates you to work in the area of TSC and mTOR?
I am fascinated by how individual cells have surveyor probes, through which they can tell whether there is food, oxygen and hormones available to them. mTOR can communicate with those probes and make an informed decision whether it should drive cellular growth and expansion when nutrients are ample, or perhaps, turn on a recycling program that would keep the cell alive in times of nutrient scarcity. TSC is one of the messengers that delivers information from those probes to mTOR. When the TSC messenger is damaged, then mTOR can no longer make good decisions, and hence we see abnormal cellular growth in TSC patients. This is something that I, as a structural biologist, can and want to help with.
I believe it is my duty to use the knowledge that we have already gathered and exercise the skills I have learned during my research training, to make a difference for people.
Scientists are very dedicated and immensely motivated people who spend their lives trying to save and benefit the world. Unfortunately, that world often cares little about what they do! Being funded by the Tuberous Sclerosis Association is a great honour to me, and it has added another level to my motivation. I feel like I have gained a thousand supporters who really care about what we do in the lab and encourage me to face the most difficult problems and questions. There is a feeling of necessity and purpose in the air, and it motivates me to achieve something that has never been done before.
You are currently based in the renowned Sabatini Lab at the Whitehead Institute, could you tell us about the important work undertaken there especially around furthering our understanding the mechanisms involved in TSC?
Prof. David Sabatini has selected an absolute dream-team of young scientists and put them together in one lab to brainstorm the most pressing questions in the fields of cellular growth control, cancer metabolism and cell compartmentalisation. I feel privileged to be a part of this team, and every day I learn something new from my colleagues who are true experts in their respective fields. A massive effort in our lab is dedicated to understanding how food resources are sensed by human cells, and how mTOR can read the information gathered by those sensors. There are two major branches of information that are directly relayed to mTOR – via sensing of nutrient levels and via sensing of everything else (e.g. energy, oxygen, growth factors, DNA damage). Those two branches have been thought to be completely independent of one another, but the most recent evidence suggests that a cross-talk between the two may exist. The “everything else” branch is very complex and is read and relayed to mTOR via the TSC protein collective. The Sabatini Lab is exploring how the TSC collective can talk to the nutrient-sensing branch, and whether there are specific mutations in TSC patients that can cause disruption in this cross-talk. Moreover, the Lab has been developing genetic and biochemical tools to study metabolism of cancer cells, and the role of individual compartments within a human cell in health and disease. These studies have yielded very exciting insights into how we can improve efficacy of certain disease treatments by adjusting our diet, or what are the vulnerabilities of specific diseases that we can exploit in our drug discovery efforts.
Your TSA funded Fellowship is transatlantic. Please could you outline these plans for our community? How will that work and what experience do you expect to get from each institution?
Indeed, this Fellowship with allow me to do something very unique, which is to work between two world-class institutes on the opposite sides of the Atlantic - in the US and the UK. mTOR itself and many other proteins that sense availability of food and control cellular growth were discovered and functionally characterised in the Sabatini Laboratory at Whitehead. As a member of this group I am in a unique position to tackle the most difficult questions related to understanding mTOR biology, and to execute a project aimed at finding ways to compensate for the defective messaging system in TSC patients. The Whitehead Institute is situated at the heart of Kendall Square in Cambridge, Massachusetts, which is called “the most innovative square mile on the planet” for a reason. Kendall Square hosts the world’s biggest hub of academia, biotech and pharma, and it is a very special place where both academic and industrial research meet. I am really lucky to be a part of this community, and my drug discovery efforts will be performed at several places in this area and surroundings.
Advancing this project into precise medicines requires obtaining a very detailed picture of how individual proteins interact with each other in their quest to control mTOR. This feat requires very specialised techniques in protein chemistry and electron microscopy that the UK’s MRC Laboratory of Molecular Biology in Cambridge has played a huge part in developing. I will seek advice of Dr Roger Williams, whose laboratory pioneered biochemical approaches to study proteins that are closely related to mTOR. With the aid of powerful electron microscopes, about which there has been a lot of buzz in the media lately, we hope to enable our drug discovery efforts, and provide support for further development of medicines against TSC.
Could you tell us a bit more about yourself outside of the lab and science?
I absolutely love playing handball as a goalkeeper. The ball is often thrown at you from a distance of 5 to 9 meters, with an exquisite precision of a hand and the speeds exceeding 60 miles per hour. Cat instincts and next-level agility are a must if you want to do well in this game. I can get really competitive playing handball, and always give my 100% on the court. During my time at UCL, we came 2nd in the British University Handball Championships, and then with Oxford we won that title twice in a row – a feat that has never been accomplished by any other university team. I also played for handball clubs in Edinburgh and London. With Gracemount Edinburgh we won both the Scottish League Trophy and the Scottish Cup, and with Olympia London we took the 3rd place in the English Premier League.
I am also an experienced yacht skipper and regularly cruise the North, Baltic and Mediterranean seas with a group of friends. Now is the time for us to explore the American waters, and perhaps attempt the challenge of crossing the Atlantic!
Finally, do you have anything you would wish to say to the UK TSC community?
I am absolutely honoured to join the UK TSC community as a Junior Fellow of the Tuberous Sclerosis Association. The UK has a number of fantastic research groups studying TSC and mTOR, and I cannot wait to be able to share and discuss my research with them. I feel very lucky to have such a great support from the TSA, and it motivates me immensely to do my 100% in the lab. We are also always looking for talented biochemistry Master’s and senior undergraduate students to join us for internships at MIT, so please let them know about us!