Ulf Landegren – Advanced detection in genomics, proteomics and clinical medicine

Progress in basic biology both motivates and enables the development of new research tools and diagnostic methods. An overarching aim of the work in our lab is to device and apply molecular detection techniques, in order to take advantage of the rapidly accumulating, detailed knowledge of the molecular make-up of humans. The purpose is to allow characterization of molecular states at high resolution, preferably for large groups of individuals. It is also a distinct ambition of our lab to make the techniques broadly available, for example via companies spun out from our lab.

Wide use of technologies

Our research group has led the development of several technologies for molecular analysis that have received wide use and many further developments by me and my students and by many others. Two central approaches that are at the basis of many of these techniques are the padlock probes and proximity assays of various descriptions.

These two concepts have been varied by my students and myself, and by many others, to address a broad range of analytical needs. Briefly, padlock probes are useful for analyses of specific nucleic acid sequences, while proximity assays are suitable to study protein expression. These two classes of molecular analyses share the ability to offer adequate specificity to identify their target molecules also in highly complex sample matrices, and a capacity to target very large numbers of molecules in parallel without loss of specificity. Yet another advantage is the ability of both technologies, when desired, to produce short, circular reporter DNA strands. This type of reaction products allow sensitive localisation and digital detection via rolling-circle amplification.

Molecular machines

The technologies that we develop can be viewed as molecular machines, composed of components that target molecules of interest via affinity reactions, coupled to enzymatic reagents that serve to enhance specificity of detection, and to signal that the probes have found their intended target molecules.

Our molecular tools are used to some extent by ourselves, and on a much larger scale by other researchers and by drug developers, to better understand important disease categories, and to probe basic biological challenges. The assays are also used to detect and distinguish diseases at the earliest possible time point, and to monitor responses to drug therapy.

Several companies spun out from the lab

As already mentioned, we are eager to see that successful techniques are being broadly applied. Besides our publications, we have licensed some of our greater than 50 patents and patent applications to leading international biotech companies, and we have ourselves spun out around ten companies, including Olink. We estimate that around 900 individuals are currently working at companies that trace their roots to our lab.

Some recent or ongoing projects in the lab:

• Multiplex versions of the in situ proximity ligation assay are used to image drug effects on signalling cascades in tumour cells, and to observe target engagement by drugs in situ.
• The highly specific superRCA technique is used for digital detection in contexts such as monitoring the course of malignant disease via liquid biopsy and to diagnose infectious disease
• Proximity assays area being adapted for highly specific and sensitive detection of plasma proteins with a view towards early detection of malignant disease.
• The antibody responses in patients are diagnostically informative in autoimmunity as well as in infectious and malignant diseases. We have developed tests of antibody specificity that enable very broad population studies, exploring reactivity towards large antigen repertoires.
• The new, effective techniques for molecular analysis motivate establishing extensive biobanks with consecutive samples, collected from very large numbers of individuals, to ensure that samples are available at various intervals before a disease becomes manifest in a person. We therefore establish a technique whereby individuals can collect blood samples themselves by pricking a finger, and where the samples are separated into cell and plasma fractions for preservation in the dried state.