More than theory: Learnings of a master’s student in life science startup
Tea Kuivala started working for LS CancerDiag as a part-time employee alongside her studies in genetics and molecular biosciences at the University of Helsinki. This international master’s program teaches how genes regulate the development and functioning of cells, tissues, and organisms. Tea sees applying to the business side as an excellent opportunity for students to learn both theory, practice, and the rules of the business world.
Tea started as a research assistant at the company and continued as a thesis worker. She did her master’s thesis within the company, where she compared research methods to investigate the functioning of the MMR mechanism, basing her work on LS CancerDiag’s DiagMMR method.
Starting as a research assistant is a fairly typical career path for students in the field. However, most do so in research groups and somewhat less often in companies. Writing a thesis within a company is inspiring; but in the business world, certain things like proprietary information need to be considered when publishing data. However, you learn to manage sensitive information, and a thesis done in such a setting becomes a unique experience which goes much beyond just scientific theory.
Company collaboration can grow students into multi-skilled professionals
Although cooperation between universities and companies are not yet that common in the life sciences, Tea expects this to change. The industry size is still quite limited in Finland, but it is expected to grow considerably. Such cooperations provide universities with great opportunities to grow multi-skilled professionals in the life sciences for companies that, like LS CancerDiag, aim to commercialize innovations in the field.
The study track that I chose was among the most recent in the master’s program and offered versatile opportunities. My specialization track in Molecular and Analytical Health Biosciences (MAB), aims to train life science experts with an in-depth understanding of the analytics of biomolecules and their functional networks in health. After completing the program, the graduates have the expertise to handle omics-based big data and combine it with an understanding of traditional laboratory testing. This omics thinking taught us how to understand the big picture, and we also got to know companies in the field through various company presentations.
Introduction of university study options should be more diversified in secondary schools
The interest in knowing things in the smallest detail, down to the molecular level, drove Tea to biosciences.
For some reason, I have always been fascinated to know what happens at the lowest level and to understand the exact chain of reactions between things. Originally, veterinary medicine was my career dream, but it was one of the easier and more familiar professions in life sciences for a young school student. Only as a result of my search did I find many other options. High schools introduce some possibilities, but this could be diversified, as finding more exotic study options requires own initiative. When the studies started, the faculty’s choice of subjects surprised me even more; there were many options that I had never heard of before.
Studying life sciences suits many types of personalities
Tea considers bioscience studies as suitable for a wide variety of personalities.
A wide diversity of personalities can be successful within the same field because various skills are needed for the whole process to work. In laboratories there is much emphasis on accuracy and to reliably repeat the same methods and analyses. On the other hand, to create visions and innovations, you also need people who can see the big picture. It is therefore good that the choice of specialization is often done later in the university studies.
In Tea’s opinion, choosing the field of specialization at a later stage of studies also supports finding the right study path eventually leading to an interesting career.
In studies, the subject of the bachelor’s thesis no longer determines the master’s studies, and options are no longer needlessly limited at a younger age. My interest in specialization changed along the way, as for most of my fellow students too, it’s good to try all kinds of things within the discipline during the bachelor’s phase, and you only need to specialize in the master’s phase; this way you can get to know everything first before making a decision.
A chain reaction opened the career path for a motivated student
Tea got hired to this role through a standard application process. While she worked part-time in a grocery store to finance her studies, she discovered that LS CancerDiag was looking for a research assistant.
I did my bachelor’s thesis on how red and processed meat increase the risk of colon cancer, which is due to lifestyle. However, LS CancerDiag investigates the heritable risk factors, and I was interested in increasing my understanding of colon cancer. After I got the job, I dove really deep into Lynch syndrome genetics. This ignited a chain reaction – previously as a student, I had not envisioned a specific future career path, but working for the company made this aspect concrete in one go. Visits to companies and industry experts could thus help students figure out their career paths. Nowadays, company employment is just as common a continuum as research work related to academia.
Thesis process within the business taught much more than theory
Tea has now completed her master’s degree, having learned the entire DiagMMR process in addition to writing a thesis. During her time at LS CancerDiag, Tea has seen all the different work phases and been involved in everything; the thesis itself focused more on the final analysis phase. In her research, she compared the efficiency of different equipment in the detection of MMR gene variant pathogenicities and investigated the automation of the process to enhance reproducibility.
The thesis was completed in May 2023 and aimed at optimizing the DiagMMR test. Dr. Minttu Kansikas was the thesis supervisor, and everything happened in close cooperation with the whole team. Doing the thesis was a great and valuable experience; it was wonderful to learn not only about the method itself from start to finish but also about people, the company, and the business world.
The aim of the study was to functionally quantify the pathogenicity of MMR gene variants found from LS individuals using DiagMMR assay coupled with fragment analysis (LabChip). DiagMMR is a functional in vitro diagnostic (IVD) test validated to distinguish reduced MMR caused by inherited MSH2 and MSH6 defects (i.e., LS) from normal MMR. The study focused on the two main MMR genes and set out to quantify variants affecting them. The efforts aimed at developing the tools assisting the early detection of LS since the DiagMMR test does not require cancerous tissue.
Specific aims of the study included:
- The functional quantification of variant pathogenicity by DiagMMR using gel and capillary electrophoresis analysis of substrate DNA
2. Evaluation of the capillary electrophoresis based Labchip as a method for MMR quantification
3. The pathogenicity assessment of MSH2 and MSH6 variants found from LS families in reference to their database classification (InSiGHT).
The company purpose motivates at work
Tea sees herself in the business world in the future and hopes for long continuity in her work.
My skills have grown enormously during this time. I have been lucky to have the opportunity to be involved in everything. I like varied work; the startup world offers variation outside of one’s core competence. Some things remain constant: processes, protocols, quality, and other standard parts related to the product, which are carefully planned, repeatable, and predictable, but changes are constantly taking place at the company level. In the growth story of a small company, you can see a cross-section of business operations that would not necessarily be visible in a larger company. I have gotten to know, for example, the construction of a laboratory and the investigation of regulatory requirements.
The importance and societal relevance of the work is a great daily motivator for Tea.
I was initially interested in colon cancer research because, as a vegetarian, I wanted to study the effects of eating meat on cancer susceptibility more closely. The genetic background of cancer naturally came into play later. Overall, the public health aspect of cancer is relevant, and the opportunity to make a difference through diagnostic test developments is essential and motivates daily.
Abstract of Tea’s master’s thesis, link to the work below.
Kuivala, Tea: Functional quantification of DNA mismatch repair gene variant pathogenicities from suspected LS individuals
Lynch syndrome (LS) is the most common cancer predisposition disease caused by dominantly inherited pathogenic variant (PV) of a mismatch repair (MMR) gene leading to a defective gene allele. The four major MMR genes encode MMR proteins – MSH2, MSH6, MLH1 and PMS2 – that participate in the proofreading and repairing of the daughter strand for mismatches after every replication. The inherited PVs predispose to cancer development as only one somatic allele loss is required for biallelic loss according to the Knudson’s “two-hit” hypothesis. The biallelic loss of an MMR-gene leads to disrupted protein function altering the MMR process. When mismatches are left unrepaired, genomic instability is caused, which can eventually lead to tumorigenesis. Especially, the risk of colorectal cancer (CRC) and endometrial cancer (EC) is increased in LS. The predisposition syndrome, LS, is important to detect as early as possible to decrease the risk of cancer by prevention and surveillance. The MMR genes and their defects vary in their consequences to the repair process considerably, and thus, it is crucial to know the different characteristics and functional effects of them when estimating the level of cancer risk. Variants of uncertain significance (VUS) are especially prevalent among LS variants. More information about their impact to the disease can be acquired by in vitro and in silico methods, for instance. The main goal of the efforts for early detection and prevention is to reduce cancer morbidity and mortality.
In this thesis, the pathogenicities of MSH2 and MSH6 variants were studied with DiagMMR assay, which has been developed for studying the protein function of these genes. In addition to the traditional agarose gel electrophoresis (AGE), the samples were also analyzed by a fragment analyzer, Labchip, that bases its function on capillary electrophoresis. This way the MMR detection efficiency of the methods could be compared. Samples were collected as skin biopsies from controls and LS patients with known MMR gene variants by Helsinki University Central Hospital (HUCH). InSiGHT database, that collects the different MMR-gene variants and their pathogenicity classification, was used to ensure that different kinds of variations, both pathogenic (class 5) and currently internationally unlisted variants, were analyzed. The skin samples were cultured to acquire primary fibroblasts for nuclear protein extraction. The level of pathogenicity was revealed by MMR-protein activity when substrate DNA with a mismatch was added to the extract. Then, restriction enzymes were used for producing fragments of different lengths, depending on the repair action, and the MMR efficiency was visualized by both electrophoretic methods. Additionally, MAPP-MMR tool was used for studying the MSH2 mismatch variants in silico.
By comparing the results from these two methods, we show that the more quantitative Labchip brings diagnostic value to DiagMMR suggesting 100% specificity (n=10) and 90,9% (n=11) sensitivity in reference to the variant information. For example, MSH6 c.3103C>T, which is listed as pathogenic in InSiGHT, was more consistent in giving an MMR deficient (dMMR) result with Labchip. Difference in the functional detection could be seen particularly with the MSH6 variants, but the differences were less notable when Labchip results were compared to the previous interpretations of the samples made based on the validated DiagMMR protocol. With the unlisted MSH6 variants, c.3139dupT was detected as dMMR by Labchip which was in unison with the previous interpretation. Another one, MSH6 c.551delA, was seen as MMR proficient (pMMR) in all the results by both the methods, and with the previous interpretation being unclear, which highlights the importance of further testing of this variant. There was also one unlisted variant (c.1805T>C) among MSH2 for which we got uniform dMMR results in two patients. The high MAPP-MMR score (25.150) for the MSH2 p.Leu602Pro amino acid change also supported the evidence gained of the pathogenic nature of this variant. As a conclusion, DiagMMR can be used reliably for MMR efficiency analysis, especially when performed together with a more quantitative analysis method.