Dr Marcin Plech on research into human hereditary diseases through deep mutation scanning

He talks about how his research could have immediate impact on the detection and treatment of genetic disorders and how this is already of great value in Mendelian disorders, how the field he is working in is still quite new and he is learning how to interpret the results of studies in the context of patient health, and the importance of peer discussion as both ideas and confidence can be gained.

Marcin graduated with a Master's degree in Biotechnology from the University of Warmia and Mazury in Olsztyn (Poland) and a PhD in Biology from Jagiellonian University in Krakow (Poland), where he studied genetic robustness and heterosis in a yeast model in the Laboratory of Evolutionary Genetics under the supervision of Prof. Ryszard Korona.

He is currently a postdoctoral fellow in the laboratories of Joseph Marsh and Greg Kudla at the Institute of Genetics and Cancer. His research focuses on investigating molecular underpinnings of Mendelian disorders, which includes developing new molecular tools and methods for screening disease-causing mutations. He enjoys training and working with enthusiastic students. Their passion is contagious and helps in crises and moments of burnout. In his spare time, he enjoys drawing, reading, and watching good old movies.

Could you briefly summarise your work?

I study human genetic diseases by deep mutational scanning, i.e. massive screens of protein variants in cell cultures, preferably in yeast. First, I create extensive sets of many thousands of variants of a disease gene, which we call libraries. In these libraries, the molecules differ only slightly from each other, i.e. they usually carry a mutation that alters one amino acid in the entire encoded protein. I then transfer these 'mutants' into the appropriate cells to test their function and/or growth. In my work, I use high-throughput screening and sequencing techniques in conjunction with protein structural analyzes and computational methods for variant interpretation and clinical prioritization.

Why is your research important? How is it relevant to people's lives?

Our research could have immediate implications for the detection and treatment of genetic disorders and affect the life expectancy of carriers of pathogenic mutations, as well as their quality of life and that of their families. The comprehensive maps of mutation effects that are a standard outcome of our experiments provide valuable information about potential outcomes in patients, including variants not previously observed in the human population. This is already of great value for early detection and correct diagnosis of Mendelian disorders. In some cases, we can perform experiments that could aid therapy, such as selecting the most effective antibodies for carriers of certain variants.

What are the major challenges in your field?

Our field of deep mutational scanning experiments is still quite new, and we are just beginning to learn how to interpret the results of our studies in the context of patient health. The most pressing challenge for me is to develop methods and analytical tools to elucidate the precise molecular mechanisms of pathogenicity of different mutations. If this can be accomplished, we will be able to distinguish between pathogenic mutations that cause loss of function, gain of function, or dominant negative effects.

What inspired you to be a scientist?

Growing up in a remote village in Poland in the pre-internet era, I spent most of my time outdoors. I always loved exploring my surroundings and observing nature. This penchant intensified during my school years until I defended my master's degree in biotechnology and later my doctorate in evolutionary genetics.

What do you like best about your job? What do you like the least?

I like the vibrant workplace culture and the opportunity to work with remarkable, passionate people from around the world.

What I do not like is the long gaps between the investment in the work and the payoff, which is not common in other professions. It often takes months or years to turn a modest piece of work at a lab bench into a comprehensive dataset that can be published.

If you could have tea with another scientist (alive or dead), who would it be? What would you talk about?

If it were a deceased scientist, I'd like to talk to Peter Dennis Mitchell, who discovered oxidative phosphorylation and proposed an elaborate model of the electron transport chain and the processes of energy production in living cells. I'd like to discuss with him the latest trends in studies of the origin of life on Earth.

One of my favourite thinkers among the living is Jaron Lanier, a former computer scientist, virtual reality pioneer, and expert on the Internet. I hope that his original and very clear thinking can offer fresh and practical perspectives on the possibilities and limitations of new AI technologies.

What is the most unusual thing you have done as a scientist?

I have assisted in surgeries on farm pigs, which are a mammalian model of early pregnancy.

If you weren’t a scientist, what would you be doing?

I just recently became a Dad and it feels like a second calling so I would consider doing it full time!

Do you have any advice for people who want to go into this field of research or start a career as a scientist?

I cannot give advice to people who have not yet made up their minds, because these important decisions should be left to them. I can, however, give a tip to those who are at the beginning of their career, who are faced with lab work and are struggling. Stay pragmatic: If an experiment does not turn out the way you hoped, or if a simple procedure fails, do not obsessively repeat it until it works. It's most likely not your fault, and you do not need to waste your time and energy that way. Instead, take advantage of happenings, take a moment to think, or discuss with your colleagues. You will be amazed at how much you can gain both in ideas and confidence.

What do you think are the major challenges facing humanity? How can science help?

One of the greatest challenges in Western countries will be demographics. The problem of the rapid ageing of our societies is extensive and complex, and I think that science and technology can be of use only insofar as they can deal with some of the consequences. Continued advances in medicine could alleviate disease, disability, and mortality rates. Technological advances could drive automation, which, combined with the prudent use of AI tools, for example, to improve logistics and management, could help halt the expected decline in living standards and perhaps even prevent it altogether for large segments of the population.