Hyperpolarization has emerged as a revolutionary technique in biological imaging and spectroscopy. The most popular technique was developed less than twenty years ago in a collaboration between General Electric and the group now known as HYPERMAG. Jan Henrik Ardenkjær Larsen is the head of HYPERMAG and one of the pioneers behind the technique. He is utilizing it to improve disease imaging, such as cancer, by building and enhancing hyperpolarization machines and MRI scanners for direct medical application.
Jan Henrik Ardenkjær-Larsen obtained his education as an electrical engineer at DTU. After completing his -master’s thesis, he pursued an industrial PhD at Nycomed, a Norwegian medical company known for producing contrast agents for X-ray, CT, and MR techniques. During his thesis at DTU, Jan Henrik primarily focused on MR, which he continued to investigate at Nycomed. His research involved electron spin resonance and nuclear magnetic resonance spectroscopies.
His PHD research involved a special technique using free radicals as contrast agents. As electron spins may enhance the NMR signal and provide contrast in the pictures, Jan Henrik studied the mechanism by which this enhances the quality of the MR images.
This technique has defined most of Jan Henrik’s career, both at the companies he has worked for, initially Nycomed, later acquired by General Electric (GE) in 2004 and during his tenure as professor at DTU since 2015.
In 2015 Jan Henrik and his group received a prestigious national grant to establish a Center of Excellence called HYPERMAG, focusing on the field of hyperpolarization of magnetic resonance.
“We already had a few grants and a large well-functioning group, so it felt like a natural step to continue and establish this Center of Excellence.” Jan Henrik explains.
The research center started as a part-time activity after they developed a new hyperpolarization machine at GE that is widely used in hospitals today and recognized as the best hyperpolarization method so far. Over the years, Jan Henrik’s group expanded, and DTU advised him to apply for the national basic research center. After an initial rejection, the center was eventually accepted, leading Jan Henrik to dedicate all of his working time to the center (2015).
Basic research centers have goals set by the universities, which are not usually end goals, and new goals often emerge along the way, facilitating the creation of new positions and knowledge within the field. Although the original basic CoE grant for HYPERMAG expired in December 2022, the center has received several other large grants including ERC and other EU grants, ensuring continued operation.
Imaging using paramagnetic substances
The electron spins that Jan Henrik has investigated has proven to play a vital role in the properties of the contrast agents used for MRI. For example, gadolinium, a paramagnetic material, has been shown to significantly alter the contrast in the MR images.
In magnetic materials there are two forms of susceptibility either positive, which are paramagnetic materials or negative, which are diamagnetic materials. Paramagnetic materials is the one most investigated in Jan Henrik’s group.
One type of paramagnetic molecules used as contrast agents are free radicals. Free radicals are organic molecules with one unpaired electron which gives them a free electron spin. However, they are extremely reactive and typically very dangerous.
The molecules that Jan Henrik is working with have their electron spin protected, making them stable. These protected electrons can be used to enhance the polarization of the nuclei, which then can be imaged in MRI scanning.
Typically, Jan Henrik’s group focuses on imaging the protons from water in the body, utilizing the paramagnetic field originating from the electron spin of the protons. Since water is abundant in the human body, they can generate relatively clear pictures. However, imaging other substances than water in the body is challenging due to the limited quantity. Thus, special techniques such as hyperpolarization, which can amplify the signal thousandfold, are required.
Apart from imaging anatomy, Jan Henrik and his group also aim to characterize diseases like cancer tumors. They take repeating pictures to observe how a disease is affected by the treatment it receives. MRI is an excellent technique for this as it is non-invasive and can be performed multiple times, unlike X-rays, which on repeated dosage can damage the tissue.
Development of new techniques
Jan Henrik, being an electrical engineer, focuses on the technology behind the MRI scanner and the preparation of contrast agents. Meanwhile, some of his colleagues concentrate on the biological aspects and the medical applications.
In Jan Henrik’s lab they constantly develop new technologies. When modifying MRI scanners, they purchase old machines and switch them to “research mode”, allowing them to freely modify the machines at their own need and responsibility. These modifications include building new coils, among other things.
The advantage of conducting these modifications at DTU is that they work independent from patients requiring treatment. Therefore, they can experiment with different techniques, which hospitals lack the capacity for.
In the laboratory, they also design hyperpolarization instruments from scratch. They acquire components from various places and design and build smaller items according to their own specifications in their electronic and mechanical workshop. For larger parts like magnets, they collaborate with an English company to manufacture them based on their design, so they can get exactly the machines they want.
Jan Henrik has also helped develop two new MRI techniques called Electron Paramagnetic Resonance Imaging (EPRI) and Overhauser Magnetic Resonance Imaging (OMRI). EPRI is a type of spectroscopy on the electrons you make images of. Since there are no free electrons in the body, contrast agents must be used to create images. Jan Henrik helped develop a new type of contrast agents designed specifically for this purpose.
“I was especially interested in oxygenation of the body tissue, that is the molecular oxygen, which you cannot measure directly with magnetic resonance. Even though there are unpaired electrons it cannot be measured on the oxygen in solution.”, he explains. During his PhD, he focused on incorporating molecular oxygen as a contrast into the images. To achieve this, he made several inventions that contributed to the advancement of this technique.
“Oxygen is an extremely important physiological parameter, it can be important to know whether the tissue or tumor is hypoxic, since it is extremely important in radiation therapy how efficient the X-rays are in killing thecancer cells and it can have great implications on how the tumor response to radiation therapy will be or if radiation therapy should be completely avoided and chemotherapy used instead.” Jan Henrik says. “OMRI is mostly the same technique, you are still using the electron spins, but instead you are using it to enhance the signal of the proton.” he further elaborates.
Collaboration within the world of hyperpolarization
Since Jan Henrik’s lab was some of the inventors of the hyperpolarization method used most often in medicine today, they have a very strong network of people around the world. He has received an ERC grant together with two other large universities, and they have many collaborators from their time as a national basic research center.
Furthermore, they collaborate with hospitals like the MR-department at Skejby and Rigshospitalet to test applications in clinical trials. They also generally have a great collaboration with the entire Hyperpolarization community in the world meeting up at international meetings. Finally they also collaborate with other groups using the technique for other applications as NMR spectroscopy and analytical techniques.
Personally, Jan Henrik is most focused on medical use, where he works with several prestigious universities such as Oxford, Harvard and Cambridge. It requires a great deal of effort to do basic research and therefore it is often the largest universities, which have the capacity to do it.
They also collaborate with several companies, the basic research center itself originated from GE Healthcare, which invented the technique and owned it originally. Today most of his collaboration with companies is still with GE, which creates the MR scanners for them. Jan Henrik has also started a company himself, which has commercialized the technique and sells it to some of the other users, which are not a target for GE. Here they are developing hyperpolarization machines, but they are also developing other technologies, including antennas capable of detecting magnetic signals and pulse sequences in NMR and MRI, which are different methods for acquiring the desired signals. These they sell commercially or to some of the collaboration partners when needed.
Strength of Danish NMR
“Within the field of MRI and the use of hyperpolarization in medical care Danish NMR are world famous and one of the leading nations. One of the reasons for this is that we contributed to the invention of the technique, a feat that have been recognized with several awards as the Laukien and Ernst price and several awards within the medical community.” Jan Henrik says.
“Danish NMR in general is also a very strong community, as we have many talented people at all universities around the country and we are good at collaborating and sharing our findings.” he finishes.
Written by: Jonatan Emil Svendsen