R&D dips - new strategies

Roughly 40 per cent of the employees in Swedish life sciences work in research and development activities. In the pharmaceutical industry though, the number of researchers has decreased from 5,806 people in 2005 to 4,262 persons in 2012. Together with academic researchers and scientists R&D departments in Sweden produce a large number of reports on clinical research and innovations, including both products and therapies.

Sweden has achieved strong positions within certain fields of research, for example cancer, cardiovascular diseases, stem cell research, implants and IT medicine.

Here are some examples of major Swedish research projects:

Cancer research/oncology
SciLifeLab: New analytical method enhances the possibility of selecting optimal cancer treatment
For a cancer treatment to be adapted to each individual patient, a large number of tumour samples need to be examined carefully. Collaboration between a company and the SciLifeLab unit at Uppsala University has now led to a method that makes this process 10 times more efficient than in the past.
New cancer treatments that target specific molecules in the tumour are under development. But for this to be effective, it is necessary to know first what mutations caused the tumour. By analyzing the sequence of genes that are often mutated in certain tumour forms, it is possible to increase the possibility of selecting optimal treatment for each patient.  

Researchers at the Department of Immunology, Genetics and Pathology at Uppsala University have been collaborating with the company Halo Genomics in a project designed to identify mutations that cause cancer of the large intestine. The scientists selected 560 genes in 192 tumour samples, and Halo Genomics produced a so-called HaloPlex™ PCR analysis that covered all the genes. The samples have been sequenced at SciLifeLab in Uppsala. The researchers expect to be able to identify exactly what molecules are affected in tumour cells from individual patients.

“With this analytical method it took a week for one person to prepare the 192 samples for sequencing, without any need for special equipment. This increases productivity by a factor of up to 10 compared with conventional methods,” says Professor Mats Nilsson, who directed the project.
 
University of Linköping: New possibilities impede tumour growth
The formation of new blood vessels is necessary for a cancer tumour to grow. Stopping this process is therefore an important goal in cancer research. Researchers at Linköping University (LiU), Karolinska Institutet (KTH) and University of Toyama in Japan have now charted the mechanism that stimulates vessel formation. The result, published in Nature Medicine, opens up new possibilities for treatment.

Researchers can show the importance of a growth hormone, PDGF-BB, and the blood protein EPO for the rise of cancer and the spread of tumours in the body. In the future, the discovery will provide new opportunities to attack tumour growth and circumvent the problems associated with resistance many of today’s medicines are subject to.
Angiogenesis is the formation of new capillaries starting from existing blood vessels. The process is one of the most important goals for treating different conditions such as cancer, obesity, cardiac disease, stroke, diabetes, and chronic inflammation. Even in healthy individuals, angiogenesis is important when healing injuries and even the menstrual cycle.  Studies carried out on mice show that when PDGF-BB binds to its receptor, the blood protein erythropoietin (EPO) is stimulated, which in turn controls the production of red blood cells. The more blood cells that are formed, the more oxygen the tumour gets, which, in turn, favours growth. The hope is that a combination of medicine targeting PDGF and EPO should be able to provide more effective treatment and overcome the tumour’s resistance to anti-angiogenesis treatment.

University of Umeå: Cannabis – the good, the evil and the ugly
Cannabis-like substances that are produced by the body have both therapeutic and harmful properties, besides their well-known intoxicating effects, and the body’s cannabinoid system may be a target for new strategies in cancer treatment. This is what Sofia Gustafsson finds in a dissertation at Umeå University in Sweden.

Intensive research is underway about whether new substances that affect the body’s own cannabinoids can be exploited for medical purposes, for instance, to relieve pain and to inhibit the growth of tumours. These are the reasons why Sofia Gustafsson studied the impact of cannabinoids on both the nervous system and tumour cells.

The body’s own cannabinoids, so-called endocannabinoids, mediate a number of different functions in the central nervous system and in the immune system and are involved in motor movement, reward effects, and learning and memory processes. Cannabinoids from the plant kingdom and synthetically produced cannabinoids affect both of these functions, all of which are mediated via cannabinoid receptors. Cannabinoids have moreover been shown to affect the fate of cells. Cannabinoids protect some nerve cells, whereas cells in certain types of brain tumours, such as glioma, are stimulated to commit programmed cell death (apoptosis).

In summary, the findings of Sofia Gustafsson’s studies show that cannabinoids can be toxic for cancer cells as well as for nerve cells, and that they decrease emryonal survival, indicating a potential of the cannabinoid system as a target system for new strategies in cancer treatment.
Lund University: New method makes it easier to treat prostate and pancreatic cancer
Laser light in combination with certain drugs – known as photodynamic therapy – can destroy cancer tumours, but is today used mostly to cure skin cancer. The reason that internal tumours are not treated with the method is that the technology does not exist to check that the precise amount of light is administered. However, software developed by researchers in atomic physics at Lund University in Sweden looks like being able to solve the problem.

“I think we are about to see a real breakthrough, both for us and for other research groups around the world who conduct research into cancer treatment using laser light,” says Johannes Swartling, Doctor of Atomic Physics at Lund University and Chief Technical Officer at SpectraCure, the company that is now developing the software.

The software’s unique feature is that it uses the optical fibres for more than simply emitting light. Intermittently they also gather information about the tumour, which they send back to the laser instrument. The hardware and software are based on patents developed by atomic physicists in Lund, led by Sune Svanberg and Stefan Andersson-Engels.

Moberg Derma: Phase II trial with Limtop against Actinic Keratosis in Germany
The German Federal Institute for Drugs and Medical Devices (BfArM) has granted the Stockholm-based company Moberg Derma approval to initiate a clinical phase II trial for Limtop. The aim is to evaluate the efficacy and safety of three different dose regimens of Limtop in a study involving 96 patients with actinic keratosis (AK) on the head or face. Actinic keratosis is sun damage to the skin that is characterised by thickening of the horny layer of the epidermis. The condition has become more common as a result of changed lifestyle and increased exposure to strong sunlight. Actinic keratosis can develop into squamous cell carcinoma and should thus be treated. Prevalence varies, as fair-skinned individuals are affected more. In populations in the northern hemisphere the prevalence is reported as being between 11 per cent and 25 per cent. The results are expected in the first half of 2013.

Limtop is an innovative formulation of imiquimod to treat actinic keratosis, genital warts and basal cell cancer. The objective is a product with short treatment duration, an improved safety profile and an efficacy similar to or better than that of competing preparations.
“Limtop has the potential to make a real difference for many patients who currently suffer significant side effects, and we look forward to evaluating this novel formulation in actinic keratosis patients,” says Peter Wolpert, CEO and founder of Moberg Derma.

Cardiovascular diseases
The Sahlgrenska Institute: Diabetes drug can prevent heart disease
The widely-used diabetes medicine metformin can have protective effects on the heart, reveals a new study conducted at the Sahlgrenska Academy, showing that metformin also has a protective effect on the heart. The study, carried out in collaboration with a research group from Naples and published in the journal Diabetes, reveals that metformin helps increase pumping capacity, improve energy balance, reduce the accumulation of fat, and limit the loss of heart cells through programmed cell death.

Karolinska Institutet: Novel microcapsules to prevent heart disease
For the past few years, researchers at Karolinska Institutet have been studying a promising approach for the treatment of cardiovascular disease, based on growth factor delivery, to stimulate new blood vessel growth from pre-existent blood vessels. Until now, no suitable combination of these growth factors together with a delivery system ensuring the development of functional blood vessels had been discovered.  The research groups, lead by Yihai Cao at Karolinska Institutet and Ebba Bråkenhielm at Inserm Unit 644, Rouen, France, have now developed a novel strategy that meets this double-edged challenge. They have developed microcapsules containing two effective growth factors, which, once injected into the cardiac muscle, prevent cardiac dysfunction.

Immunology and environmental impact
The Sahlgrenska Academy: Researchers may resolve the antibiotic-resistant bacteria dilemma
Antibiotic-resistant bacteria continue to be a global concern with devastating repercussions, such as increased health care costs, potential spread of infections across continents, and prolonged illness. However, researchers at Sahlgrenska Academy and Harvard Medical School have identified pathways of naturally-occurring molecules in our bodies that can enhance antibiotic performance.

Mice infected with Escherichia coli (E. coli) or Staphylococcus aureus (S. aureus) bacteria were given molecules called specialized pro-resolving mediators (SPMs) along with antibiotics. SPMs are naturally found in our bodies, and are responsible for mediating anti-inflammatory responses and resolve inflammation. The researchers found that specific types of SPM molecules, called resolvins and protectins, were key in the anti-inflammatory response to limit tissue damage by stimulating the body’s white blood cells to contain, kill and clear the bacteria.

RvD5 – a type of resolvin – in particular was also helpful in regulating fever caused by E. coli, as well as counter-regulating genes responsible for mounting excess inflammation associated with infections; hence, limiting the collateral damage to the body while fighting infection. When Dr Nan Chiang, BWH Experimental Therapeutics and Reperfusion Injury Center, and lead study author, added these natural mediators together with antibiotics, fewer antibiotics were needed. This demonstrated for the first time that stimulating resolution programmes can limit negative consequences of infection.
According to the researchers, another advantage of SPMs is that, unlike anti-inflammatory drugs (e.g. aspirin, steroids, ibuprofen), SPMs do not cripple the body’s normal immune response.

Uppsala University: High levels of phthalates can lead to greater risk of diabetes
There is a connection between phthalates found in cosmetics and plastics and the risk of developing diabetes among older people. Even at a modest increase in circulating phthalate levels, the risk of diabetes is doubled. This conclusion is drawn by researchers at Uppsala University in a study published in the journal Diabetes Care.

“Although our results need to be confirmed in more studies, they do support the hypothesis that certain environmental chemicals can contribute to the development of diabetes,” says Monica Lind, associate professor of environmental medicine at the Section for Occupational and Environmental Medicine.

In a physical examination participants were examined for fasting blood sugar and various insulin measures. As expected, diabetes was more common among participants who were overweight and had high blood lipids. But the researchers also found a connection between blood levels of some of the phthalates and increased prevalence of diabetes, even after adjusting for obesity, blood lipids, smoking, and exercise habits. Individuals with elevated phthalate levels had roughly twice the risk of developing diabetes compared with those with lower levels. They also found that certain phthalates were associated with disrupted insulin production in the pancreas.

Neurology
Linköping University – First to survey the genes of the fruit fly
How are 100 billion cells created, each with specific duties? The human brain is evidence that nature can achieve this. Researchers at Linköping University (LiU) have now taken a step closer to solving this mystery.

“Knowledge about the mechanisms that diversify neurons and sustain their diversity is necessary in order to cultivate and replace nerve cells in the future,” says Mattias Alenius, Assistant Professor of Neuroscience, who has published his research breakthrough in the March 2012 issue of the journal PLoS Biology.

Alenius and his research team at the Department of Experimental and Clinical Medicine at LiU studied the fruit fly’s olfactory system, which consists of 1,200 olfactory neurons (humans have six million) divided into 34 groups. Each group responds to a particular set of odours, since all the neurons of the group use only one of the olfactory receptors present in the fly’s antennae. Together, the receptors provide the fly with the ability to distinguish between thousands of odours: one olfactory receptor – one neuron group.

Alenius and his colleagues are the first to go through all of the fruit fly’s 753 gene regulatory genes, called transcription factors. They have identified a set of seven factors that, in different combinations, are required to create each of the 34 neuron groups in the antenna. A surprising finding is that most transcription factors perform two tasks simultaneously: they can activate odorant receptors’ expression; while at the same time deactivating others in the same cell. Alenius explains: “This is one of the many tricks that is useful to know for the future if you want to make and cultivate each of the many thousands of nerve cell groups that make up our brains.”

Uppsala University: Genetic adaptation of fat metabolism key to development of the human brain
About 300,000 years ago humans adapted genetically to be able to produce larger amounts of Omega-3 and Omega-6 fatty acids. This adaptation may have been crucial to the development of the unique brain capacity in modern humans. In today’s life situation, this genetic adaptation contributes instead to a higher risk of developing disorders like cardiovascular disease.

The human nervous system and brain contain large amounts of polyunsaturated fatty acids, and these are essential for the development and function of the brain. These Omega-3 and Omega-6 fatty acids occur in high quantities in just a few foods, such as oily fish. Our bodies can also produce these important fatty acids themselves from certain vegetable oils.

In a new study led by researchers at Uppsala University and published in The American Journal of Human Genetics Swedish scientists have investigated the genes for the two key enzymes that are needed to produce Omega-3 and Omega-6 fatty acids from vegetable oils. This unique genetic variant appeared some 300,000 years ago in Africa and has probably been an important factor for human survival in environments with limited dietary access to fatty acids.

“In today’s life situation, with a surplus of nourishment, this genetic adaptation contributes instead to a greater risk of developing disorders like cardiovascular disease,” says Adam Ameur, a bioinformatician at the Department of Immunology, Genetics and Pathology.  “This is the first study to show a genetic adaptation of human fat metabolism. It’s also one of few examples of a so-called ‘thrifty gene,’ that is, a genetic adaptation that contributed to enhanced survival in an earlier stage of human development, but in a life situation with an excess of food instead constitutes a risk factor for lifestyle diseases,” says Ulf Gyllensten, professor of medical molecular genetics at the Department of Immunology, Genetics and Pathology.

Karolinska Institutet: New knowledge on the pharmacology of dopamine stabilisers
A study from Karolinska Institutet shows that a new drug for Huntington's disease – pridopidine or dopamine stabiliser ACR16 – might operate via previously unknown mechanisms of action. Researchers have found that at very low concentrations, ACR16 binds to the sigma-1 receptor, a protein in the brain important to neuronal function and survival. This new knowledge can be used to develop future treatments for schizophrenia, involuntary Parkinsonian tremors and neurodegenerative diseases.
"It's conceivable that some of the beneficial effects of dopamine stabilisers are mediated via the sigma-1 receptor," says principal investigator Daniel Marcellino of the Department of Neuroscience. Dopamine stabilisers are a new class of drug substance originally developed by Swedish Nobel laureate Professor Arvid Carlsson. In clinical trials, these substances have revealed promising results against neurological and neuropsychiatric conditions that currently lack suitable treatment, such as schizophrenia and the dyskinesia (involuntary tremors) caused as an adverse effect of Parkinson's drugs. Pridopidine (also known as Huntexil), is in an advanced phase of clinical trials (phase III) for the relief of the motor symptoms of Huntington's disease. There is currently only one drug registered for the relief of Huntington's symptoms, but as it has several adverse effects there is a strong demand for alternative treatment options.

Medical technology
University of Uppsala: Smart bio material can heal bone
How do we get something to grow out of nothing? This is what the polymer chemistry team at the Department of Chemistry at Ångström Laboratory of Uppsala University is discovering at great speed. Their findings mean that soon we will not have to be operated on to heal severe bone fractures or burn injuries. All we will need is an injection.
Sonya Piskounova´s dissertation on smart biomaterial represents so-called regenerative medicine, which is a discipline about developing new biomaterials and methods to get human bone, cartilage, nerves, and skin to heal itself. Regenerative medicine is based on interdisciplinary collaboration. Besides chemists, Sonya Piskounova´s team includes biologists, medical researchers, surgeons, and materials scientists. Sonya Piskounova is concentrating on the creation of new bone tissue with the aid of a biomolecule called BMP-2, which is a protein that makes bones grow. The problem with BMP-2 is that it breaks down in the body in just a few minutes.

“What’s new, and what I show in my dissertation, is that by having a gel-like substance carry the protein, a so-called hydrogel, you can control both how and where the new bone is to grow,” explains Sonya Piskounova. One advantage is that you can avoid open surgery and decrease the risk of infections and other complications. Applications in health care include both healing complicated bone fractures and growing bone tissue where there is too little or none at all. Clinical testing is already underway at Karolinska University Hospital. Sonya Piskounova is convinced that the new method will be applied at hospitals within 10 years.

KarolinskaInstitutet:  Research breakthrough for drugs via the skin
A research team at Karolinska Institutet has succeeded in describing the structure and function of the outermost layer of the skin – the stratum corneum – at a molecular level. This opens the way not only for the large-scale delivery of drugs via the skin, but also for a deeper understanding of skin diseases.

"You could say that we've solved the puzzle of the skin barrier, something that has great potential significance for dermatology," says principal investigator Lars Norlén, associate professor at Karolinska Institutet's Dermatology and Venereology Unit. This will hopefully enable the widespread administration of drugs though the skin instead of via pills or injections, which brings several advantages; for example, it means that drugs can be delivered evenly over time instead of in doses, and patients bypass the first-passage metabolism, whereby the entire dose passes the liver, thus increasing the risk of adverse effects. "This may be a breakthrough for dermatology," says Dr Norlén. "Our team has devoted the past 20 years to unlocking the mysteries of the stratum corneum."

Lund University: Cultured muscle cells
Patients who have been injured in an accident or suffered from a particular muscular disease sometimes need plastic surgery to regain their appearance and their muscular function. Currently, muscular tissue is taken from other parts of the body to be used as a filler, but with the use of cultured tissue, patients would be spared the additional operation.

At Lund University researcher Linda Elowsson uses scaffolds made of blood and plasma.  “A great advantage of this is that it should be possible to use the patient’s own blood. If one then also uses muscle cells grown from a small tissue sample from the patient him/herself, the risk of rejection becomes minimal,” she says.

The blood-based scaffolds were developed by Harald Kirsebom from the Department of Biotechnology. He uses a "cryogel" technology in which diluted blood is polymerized in a frozen state and is thereby transformed into a porous, sponge-like material. So far, the cell culture is taking place in a sort of test tube. If the technique is successful, larger containers could be tried in the future.  “There are many research teams in different places working on tissue culture – "tissue engineering" – when it comes to cartilage and bone. There are nowhere near as many working on muscles, precisely because they present a considerably greater challenge,” says Linda Elowson.

Sensidose: New individualized dosage system ready for market launch
Sensidose AB in Uppsala has in co-operation with the Department of Neuroscience, (Neurology unit) at Uppsala University developed a totally new and patented system for individualized dosing of drugs in tablet form. An electronic dosing device that makes it possible to administer drugs in the form of microtablets is a central part of the system. Functions for symptom registration are also included.

“In certain disease conditions a carefully individualized dosing of pharmaceuticals is important for an optimal treatment effect. This applies to conditions where the positive effect is balancing on a thin margin between underdosing with no effect and overdosing with troublesome side effects. Sensidose has developed and patented a system where the dosage can be fine-tuned by means of microtablets and an electronic device similar to a mobile phone. The patient can also use this device to register the dose, the effect and any side effects. This information can then be transferred to the responsible doctor or nurse,” says Sten Magnus Aquilonius, professor emeritus and member of the board of directors at Sensidose.

The system from Sensidose covers great medical needs. Up to 90 per cent of the three million patients in the world suffering from Parkinson’s disease may benefit from the drug.

International co-operation
According to the policy of the Association of Swedish Researchers there are three objectives for international co-operation:

Swedish researchers should actively participate in international research collaboration.
Sweden should be an attractive, international forum for exchanging ideas in basic research.
Sweden should be an attractive workplace for foreign researchers

The foundation for international co-operation in life sciences is an intense collaboration between Sweden and its Nordic neighbours, best symbolized by the Medicon Valley concept in Lund, a bridge between life-science companies in Denmark and Sweden.

An important part of the internationalisation work is to attract large, global conferences about health-related issues. Sweden also works actively to increase the number of international clinical studies performed. Swedish hospitals are also very active partners in EU-funded life-science projects and a number of researchers from countries outside Europe work at the major university hospitals.

Integrity, honesty, ethics
Whether on a corporate, academic or public level the Swedish culture is founded on a strong sense of integrity, honesty and ethics. There is extensive experience of integrating ethical aspects in decision making. With regard to clinical trials, for example, Swedish ethics reviews committees are of a very high standard.

The Swedish Research Council, Vetenskapsrådet, monitors ethical guidelines, especially for medical research, which is highly regulated. Research ethics also touches on questions such as how to behave towards colleagues, responsibilities to financial partners, the researcher’s role in society (e.g. as an expert) and which subjects should be studied. To avoid fraud and misconduct a code has been drawn up to guide the researchers in their ethics discussions.

On 1 January 2004 the Swedish Act concerning the Ethical Review of Research Involving Humans (SFS 2003:460) was introduced. The law applies to situations such as research that involve physical encroachment on a subject or are conducted according to a method that aims to affect the subject physically or psychologically, as well as studies on biological material traceable to specific individuals. It is fundamental that research only be approved if it can be conducted with respect for human dignity and if human rights and fundamental freedoms are constantly safeguarded. A person’s welfare should be prioritised over the needs of society and science. Research that clearly involves a risk of harming subjects, for example interviews or surveys, should also be examined ethically.

Patents and product rights
The situation concerning patents for life science-related inventions in Sweden is not different from any other European Union member state. The application made to the Swedish Patent and Registration Office (PRV) may also be made in English to prepare further international patents. One famous Swedish patent is the “Steel kidney” by Nils Alwall. This doctor from Lund invented a dialysis machine which has been a great international success and the driving force behind the company Gambro, which was founded by Holger Crafoord in the 1960s. Two other famous Swedish medical patents are the “Brånemark” titanium screw and the osseointegration method, which is used for fixing limbs and teeth, and the blood rocker, a device for preventing blood from clotting in the clinical laboratory, which was invented by Barbro Hjalmarson, a nurse.

The alternative is to protect a design, which gives exclusive rights, for example for a dental chair or a tablet shape. This has been successfully applied by AstraZeneca.