For 50 years, the Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology (IKP) in Stuttgart has been studying the effects of drugs. The personalized therapies developed at the IKP are saving lives today – and will revolutionize medicine even further in the future.
When Dr. Kerstin Bühl, a geriatric internist at Robert Bosch Hospital (RBK), first met her patient Ilse Berger (name changed), she immediately had a specific suspicion. The 88-year-old woman had been admitted to hospital with a fractured femur and was taking 13 different medications – for heart failure, diabetes, high blood pressure, and atrial fibrillation, painkillers for osteoarthritis, antidepressants, and the cholesterol-lowering drug statin. At RBK, it is standard procedure for geriatric specialists to be consulted at an early stage in the case of elderly patients with multiple illnesses and a fracture. "When so many medications are taken at the same time, there is a high likelihood of adverse interactions with clinical symptoms," Kerstin Bühl explains. During the patient interview, she also learned that Ilse Berger was not only experiencing pain from the fracture, but also muscle pains all over her body. "The patient's muscle pains suggested that there was a problem with the statin."
Fortunately for this patient, no hospital is as well prepared for such situations as RBK on the Bosch Health Campus in Stuttgart.
If there is any suspicion of hereditary causes for adverse drug reactions after a patient has been admitted at RBK, their genetic material is analyzed. This standardized DNA check was introduced several years ago in cooperation with the Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology (IKP). "In medication, the principle of 'one size fits all' still applies: one drug is prescribed for all people suffering from a certain disease," says Prof. Dr. Matthias Schwab, the IKP Director. "But people react quite differently to drugs because of their varying genetic makeup. If certain hereditary dispositions exist, drugs can have a stronger or weaker effect – or trigger serious side effects." At RBK, a patient’s genome is examined for numerous gene variants that influence more than 35 commonly used drugs. Patients receive this critical information in a Medication Passport app that is valid for their entire lifetime and designed to the highest data protection standards. In a highly regarded study, IKP researchers who collaborated with an international team were able to show at the beginning of 2023 that the Medication Passport can reduce a patient’s side effects by around 30 percent.
The Medication Passport is a good example of IKP’s work and mission. The institute was founded 50 years ago as a result of a donation from Dr. Margarete Fischer-Bosch, Robert Bosch’s eldest daughter. Back then, only four members of staff were working at the institute; today, there are about 70, most of them experts in the fields of medicine, genomics, metabolism, and bioinformatics. "Besides developing new drugs, clinical pharmacology is primarily concerned with investigating how the human body or tumors react to established substances," says Matthias Schwab, who has headed the institute since 2007.
In the past two decades, the institute’s research has increasingly focused on pharmacogenomics, a discipline with an even longer tradition at the institute. As early as 1975, Prof. Dr. Dr. h.c. Michel Eichelbaum, who was then the IKP Director, identified the so-called CYP2D6 polymorphism. A gene mutation present in about ten percent of the European population means that for women, for example, a highly effective drug against breast cancer, tamoxifen, does not have the desired efficacy. For such patients, the dose may need to be adapted or an alternative drug used to prevent them from developing breast cancer again. The institute presented, at an early stage, fundamental research work on this gene mutation. Research is currently underway on a drug that will enable such women to still use tamoxifen. But it will be several years before this drug reaches market maturity.
At the heart of the institute’s research work are genome analyses that are carried out with sequencing machines and the results produced in data form. Researchers can interpret a patient’s genetic disposition from a seemingly endless series of numbers and letter abbreviations and recommend appropriate medication. Nowadays, a genetic analysis can be produced within a few days.
Another focus of the institute’s work is pharmacotherapy in oncology. "The more we know about the genome of a diseased person and the genome of the tumor, the more targeted our treatment can be," Matthias Schwab explains. The short distances on the Bosch Health Campus greatly facilitate this approach. Tissue samples taken from patients at Robert Bosch Hospital during routine procedures such as cancer surgery are analyzed at the institute once patients have provided the required information and given their consent. "In some cases, we succeed in turning cancer into a chronic, but no longer acutely life-threatening disease through therapies tailored to the individual genome of the patient and tumor," Matthias Schwab says. This kind of personalized medicine has dramatically improved the treatment possibilities, especially for lung cancer. The institute's top priority is translation, i.e., the rapid transfer of the latest research findings to the patient’s specific case. However, Matthias Schwab is fully aware that, especially with cancer cases, it is not yet possible to help that many patients, or only to a limited extent.
This is another reason why the IKP’s motto is the same now as it was 50 years ago: research, research, and more research to develop drugs faster and make them more successful. "Only less than ten percent of the active substances tested in clinical trials reach market maturity," says Prof. Dr. Volker Lauschke, who heads RBK’s Microphysiological Tissue Models Research Group. Animal studies produce many false-negative or false-positive signals. "A rat liver is very different from the organ of a human being who has had an excessively fatty diet over a long period of time and also developed high blood pressure and diabetes, for example," Volker Lauschke points out. That is why his research group creates 3D cell aggregates – so-called spheroids – in a nutrient solution from human liver cells taken by biopsy from diseased individuals. "These cell spheroids provide more realistic test results," he adds, "because they carry a person's life history and better mimic cell interactions in real organs." The researchers use a fine pipette to place the spheroids, which are up to 200 µm in size, into the 96 wells of a tray. Then, each "mini-liver" is confronted with a different substance in a special apparatus and the results analyzed. "As we can fill a tray in a few minutes, it is possible to test up to 10,000 different molecules in an enormously short time," he points out.
A major project at IKP is currently focused on finding promising molecules for a drug to treat inflammatory fatty liver. In industrialized countries, 20-30% of the population suffer from this disease, for which there is currently no effective drug. Using chemogenomic screening with spheroids, IKP researchers have succeeded in identifying a promising group of active substances. The next step, Volker Lauschke says, is to continue developing appropriate drug molecules to withstand the pH in the stomach. "Over the past decade, we’ve made tremendous progress in 3-D cell models," he adds. During the pandemic, it thus proved possible to identify the efficacy of a compound that actually reduced mortality in patients by 25 percent and is now being deployed as a drug. "As a result of the pandemic, we were able to move quickly into the field," he explains and hopes "that such successful case studies will lead to the findings from 3-D cell tests being more quickly recognized by regulators and verified in clinical trials, the initial investigations of a new substance in humans." After all, the challenge is not just to develop and perfect the technology. Social acceptance and incorporation into the healthcare system are just as necessary.
Of course, this also applies to the Medication Passport, which in Germany is currently only a standard procedure at Robert Bosch Hospital. Matthias Schwab would like to see it soon become established practice across Germany. Since the data are only stored by the patient in the app and not in some centralized database, no tedious, in-depth data protection debate is expected. This would improve the way patients can be provided with suitable medication. After all, it is not only Robert Bosch Hospital that has patients who could be given personalized treatment or treated with fewer drugs.
That is exactly what it came down to in the case of the geriatric patient Ilse Berger. "Statins are highly effective drugs that prevent for example, heart disease or strokes,” Matthias Schwab says. "But some people’s genetic disposition impairs the functioning of a transport protein. Anyone with this mutation has an enormously high risk that certain statins will cause a pathological and painful muscle breakdown."
So it is important to analyze the medication regimen, which in cases like this one means involving the expertise of drug therapy specialists, or clinical pharmacologists as they are known. This is directly possible because of RBK’s unique location on the same Bosch Health Campus as the Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology.
The elevated muscle enzyme values in Ilse Berger’s blood were what aroused the suspicions of the geriatric specialist Kerstin Bühl. When she and Matthias Schwab took a closer look at Ilse Berger's genetic findings, her suspicions were confirmed. But what could be done? After all, statins cannot simply be discontinued. "Statin medication is regulated in therapy guidelines that are also binding for those treating the patients," Kerstin Bühl explains. And here, the short distances at the Bosch Health Campus came into play again. Through cooperation with IKP’s Clinical Pharmacology Department, RBK physicians can adjust a statin therapy and select a drug that can be used without any risk despite the existence of this gene modification. In addition, an analysis of the medication schedule and Ilse Berger’s genetic makeup meant that the number of medications prescribed could be reduced from 13 to nine. When looking at the list of medications she took every day, Matthias Schwab noticed that one painkiller was partially cancelling out the effects of the antihypertensives. Especially with geriatric patients, this form of interaction has to be taken seriously. The complex interactions of the drugs with their possible clinical consequences are not always correctly assessed by treating physicians.
For Matthias Schwab such know-how is part and parcel of his daily work as a clinical pharmacologist. In Ilse Berger's case, an alternative painkiller helped to permanently control her blood pressure. And although Ilse Berger will not fully recover from all her ailments (like many other geriatric patients), she now has the best drug therapy imaginable – as individual as she is herself.
Although the name might suggest otherwise, clinical pharmacology is not primarily concerned with the development of new drugs but examines exactly how existing medicaments act on a human organism. This is because not all drugs have the same effect on every individual. Irrespective of age and possible previous illnesses, a person’s genome determines whether and how a drug works, and what side effects it will have. This means that while a drug may have the desired effect for most patients, in some it will be less effective or have no effect at all. In extreme cases, the genetic makeup may even result in a drug having fatal side effects. Clinical pharmacology aims to provide the most appropriate and efficient therapy for all patients.
Currently, research is mainly focusing on pharmacogenomics, i.e., the influence of genetic information on the efficacy of drugs. A particular focus here is oncology. This involves not only the human genome, but also the genome of the respective tumor because tumors also respond individually to therapies. State-of-the-art technology is deployed in studying this field of research at IKP, which currently employs about 70 people. For example, artificial mini-tumors – so-called organoids – are grown in a nutrient solution to simulate how tumors behave in the human body or under the effect of various drugs. IKP cooperates in its research work with numerous renowned institutions, such as the Karolinska Institute in Stockholm or the St. Jude Children's Research Hospital in Memphis, USA.
Personalized therapies, i.e., drugs adapted to a patient’s genome and their (medical) history, are becoming more important in many areas. The advances are currently most evident in cancer therapies because the latest generation of cancer drugs, known as inhibitors, are very specific and only work, for example, if the tumor has certain mutations. To this end, it is also necessary to examine the genome of the tumor, from which a sample is taken using a thin hollow needle.
For a long time, the findings of research work in laboratories were only published in scientific journals. And it often took years before they were implemented in therapy. The so-called translation concept solves this problem by enabling the latest research findings to be immediately transferred into forms of treatment. Patients make their genome and tumor data available to researchers and can then benefit from the latest, and often still experimental, therapies. The fact that IKP and Robert Bosch Hospital are both on the Bosch Health Campus and cooperate closely plays a decisive role here. Patients do not have to wait long for the findings as they are often available within a few days. This enables an immediate response and appropriate therapy.
First, a blood sample or a biopsy of the diseased tissue is taken. Then the genome of the patient or tumor is sequenced and evaluated in IKP laboratories. If more complex analyses are required, IKP and Robert Bosch Hospital cooperate with the Human Genetics Department at Tübingen University Hospital. The next-generation sequencing method used there enables millions of DNA fragments in a sample to be examined in parallel. Remarkable advances have already been achieved: Up to a few years ago, only 300 genes of relevance to personalized therapy could be examined. Now, there are 23,000.
When patients check in at Robert Bosch Hospital, their individual genome is analyzed as a standard practice. This involves checking 50 gene variants that can influence the effects of 39 drugs. The individual medication can then be optimally adjusted. A highly regarded international study published in the renowned scientific journal Lancet showed that side effects could be reduced by 30 percent in this way. Since a person's genetic information does not change over the course of their lifetime, it is stored digitally and made available to the patient in encrypted form in an app. Throughout a person's life, this so-called Medication Passport can then be consulted prior to any treatment and medications individually adjusted.