Researchers ask nature for help in search for new medicines

Researchers ask nature for help in search for new medicines

Both researchers are specialists within biotechnology and were recruited by the department in 2018 as an important step in the department’s efforts to strengthen research and collaboration within medicinal fields. The two researchers are highly specialised within their respective fields – the identification and creation of antibodies and model-organism-based studies of gerontology and age-related diseases – and both apply them in a variety of research projects.

- “What characterises both mine and Peter’s research is that in everything we do, we ask nature for help. Like most other scientists, we set out a research hypothesis and work to prove it. However, we take a completely open and unbiased approach and apply screening and selection strategies in order to figure out, for instance, what causes a specific condition or disease, or what specific antibody works on what kind of cancer cell and how that antibody has been created. This open approach means that our methods and technologies can be used in a wide range of research contexts – and a wide range of fields” Anders Olsen says.

USING MODEL ORGANISMS TO STUDY AGEING

Anders Olsen’s main field of study is gerontology and age-related diseases, and for this purpose he uses what is called a “model organism” in order to be able to study processes that would otherwise take several years.

“If you want to study the ageing process or slowly developing, age-related diseases in humans, who may grow to be 100 years old, you will need to be quite patient. Therefore we use model organisms instead, in our case the model organism called C. elegans. This is a small, see-through worm that has a life span of 20 days, which helps quite a bit in terms of the patience you need while studying them” Anders Olsen explains with a smile.

Among the topics that the researchers are able to study through this model organism is why some individuals age faster than others. For this purpose, they use a range of genetic tools and modifications.

- “In recent years, research has shown that you can change the C. elegans worm’s genome and create mutants with a markedly longer life span. We have one mutant in our lab where we have changed one gene and doubled its life span, and if we change two genes, we have shown that we can make it live as much as 100 days. And to put things very simply, what we are working on is understanding why: What is the difference between a mutant that lives for 100 days and an ordinary C. elegans worm that lives for only 20 days? And then we apply a range of biotechnological tools in order to identify and understand what has caused changes that happen in these worms. So far, we have shown that it is not one single thing but rather a combination of different bio-chemical pathways, for instance changed fat metabolism and changed insulin delivery, that causes these differences in the worms’ life spans”.

STUDYING WORMS WITH ALZHEIMER’S, PARKINSON’S AND HUNTINGTON’S

In addition to studying the ageing process and what impacts life span, the C. elegans worms also enable the researchers to build different models of humane diseases. “In our research here, we focus on age-related and especially neurodegenerative diseases, which means that we have worms that get Alzheimer’s disease, worms that get Parkinson’s disease and worms that get Huntington’s disease. In these studies, we utilize the fact that the worms’ nervous system is a lot simpler than ours, which enables us to study both what might cause these diseases and how we can prevent or treat them” Anders Olsen explains. By using C. elegans and the associated biotechnological tools to understand such processes means that the methods have a very wide applicability.

- “We collaborate with various research groups who work on challenges where we can build models in C. elegans and in that way use genetics and genetic screening to understand how and why various processes work. For instance, we collaborate with researchers who work with probiotic bacteria, bacterial diseases and the importance of intestinal bacteria for our health, and we collaborate with neuro psychologists. The model organisms open up for all kinds of collaboration across sections, departments and fields, and being able to apply our methods in this way is incredibly interesting and holds almost unlimited potential” Anders Olsen says.

WORKING TO FIND A CURE FOR CANCER

While Anders Olsen mainly works with gerontology and age-related diseases, his colleague Peter Kristensen spends the majority of his time on a disease that occurs at all ages: Cancer. His research focuses on methods for the creation of antibodies that can target specific forms of cancer cells.

- “One of the challenges with diseases such as breast cancer or colon cancer is that there is a very high degree of heterogeneity, not only from patient to patient but also within each patient. This means that if two women are diagnosed with breast cancer, the general opinion is that they have the same disease. However, this is not actually the case. Breast cancer varies markedly from one patient to the next – and that is highly significant for the kind of treatment each patient needs. Therefore, treatment needs to be targeted to the specific type of breast cancer that the individual patient has, and this is why we need to work with what is known as personalized medicine” Peter Kristensen says. Today, cancer is usually treated through a combination of surgery – to remove the initial tumour – and chemotherapy, which kills the majority of the dividing cancer cells that cause the tumour and metastasis to spread. However, some cancer cells may stop their division – essentially becoming dormant, until they start dividing again later. This means that chemotherapy will not kill them, and such dormant cells are the reason why some patients experience a relapse later. The challenge for the researchers is to figure out how to get rid of these non-dividing or slowly-dividing cancer cells so that they can cure patients completely. Peter Kristensen explains:

“In order to kill such cells, we need to know which surface markers are specific to them. And once we have identified these surface markers, we need to first identify antibodies that will target them, and secondly be able to produce these antibodies at a large scale – at which point we can start treating patients.”

FROM SINGLE ANTIBODY TO EFFECTIVE TREATMENT

It is of course a long process from the day the researchers identify antibodies that work and until the day these antibodies can be used to treat patients – maybe as much as 10 years. And the researchers face a number of challenges along the way.

“Our bodies are capable of creating millions of different antibodies. In our DNA, we have genes that include the code for creating these antibodies, and we can isolate these genes and extract them so we can work with them in the lab. If, then, we have a pool of genes, we can create a pool of antibodies – proteins – but only one single one will work on the cancer cell. In addition, if we want to be able to treat and cure patients, we need a lot of this exact antibody, and the challenge is to identify which gene holds the code for it so we will be able to mass-produce it” Peter Kristensen explains.

This challenge is connected to what is known as the “central dogma” of molecular biology: You have DNA on the one hand and an antibody (a protein) on the other hand – and in between, a messenger called messengerRNA. You can identify the messengerRNA from the DNA, and you can identify the DNA from the messengerRNA – but once you take the next step from messengerRNA to the protein, you lose the ability to identify the process backwards. In other words: You cannot identify the gene from the protein.

- “What we do here is try to short circuit this dogma by creating a physical connection between a specific gene and the protein/antibody created by that gene. In order to do this, we use a virus called filamentous bacteriophages. In essence, a virus consists of DNA surrounded by a “shield”, called a capsid, consisting of proteins. The genes containing the code for these proteins are present in the DNA. If we then take a gene for an antibody and insert that into the virus DNA in connection with one of the capsid proteins, the DNA will start creating the antibody along with the capsid protein, and we end up with a virus particle with the antibody on its surface” Peter Kristensen explains. At this point, the researchers have both the antibody AND the DNA inside the virus particle that has created the antibody, in other words, a physical connection between the DNA and the antibody.

- “Once we have made this connection, we can start working with a million different virus particles, each with a specific antibody on its surface. Then we combine these virus particles with our slowly-dividing cancer cells, wash away all the virus particles that do not attach to the cells – and what we have left are virus particles that attach to the cancer cells because they have an antibody on their surface that recognises and attaches to the specific surface markers of that cancer cell” Peter Kristensen explains.
“And most importantly: not only do we at this point have the effective antibody that latches on to the surface markers – we also have the gene that created that antibody. This means that we can start producing a lot of that antibody, and in combination with now also being able to identify the surface markers of non- or slowly-dividing cancer cells in thousands of patients, this means that we can create targeted, effective treatment that can hopefully cure them” he finishes.

AIMING FOR A HEALTHIER OLD AGE

While such work leads to some people seeing “old age” as just another disease that should be cured so we will be able to live forever, both researchers agree that this is not the case.

- “When talking about research in gerontology and age-related diseases, a significant point is that we do not see ageing as a disease that we are trying to cure. We work to understand how the ageing processes work, and we work to understand how diseases work and how we can cure them, but it is very important to make the distinction between our life span and our health span” Anders Olsen emphasises.

- “Some researchers believe that the mechanisms that lead to ageing are also the mechanisms that lead to some of the common diseases, and so if we can understand these processes and delay the ageing process, maybe we can delay or get rid of the diseases as well and be healthy for a longer time. And there is evidence to both support and deny that point – I believe that you can grow old without getting sick and weak, and we do see more and more people who parachute at the age of 80, for instance. To me, the aim of the work we do here is to enable people to grow old but still be active, healthy and independent” he finishes.