#5 The BugDrug Project

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A large number of patients do not respond well to commonly used drugs. Some patients even suffer from side effects. In Europe alone, about 3.5% of hospital admissions are related to side effects of medicines. Many patients are not treated properly because they do not respond or respond poorly to medicines.

In this episode, I will talk to Professor Fu. As a recipient of the ERC Consolidator Grant, Dr Jingyuan Fu offers a solution to this problem by changing the bacteria that live in the guts of humans.  Professor Fu researches whether the effectiveness of medicines can be improved by making adjustments to the whole of micro-organisms in the gastrointestinal system (intestinal microbiome). Besides her project, we will also speak about her background in academia, the ERC Consolidator Grant and the Organ-on-a-chip Initiative.

A large number of patients do not respond well to commonly used drugs. Some patients even suffer from side effects. In Europe alone, about 3.5% of hospital admissions are related to side effects of medicines. Many patients are not treated properly because they do not respond or respond poorly to medicines.

In this episode, I will talk to Professor Fu. As a recipient of the ERC Consolidator Grant, Dr Jingyuan Fu offers a solution to this problem by changing the bacteria that live in the guts of humans.  Professor Fu researches whether the effectiveness of medicines can be improved by making adjustments to the whole of micro-organisms in the gastrointestinal system (intestinal microbiome). Besides her project, we will also speak about her background in academia, the ERC Consolidator Grant and the Organ-on-a-chip Initiative.

[00:00:01.500] Claire Selbeck NIN

Welcome to the fifth episode of Innovation Matters, a podcast organized by the Netherlands Innovation Network. In this episode, we’ll talk about a research called Bug Drug or enhancing the efficacy of commonly used drugs by manipulating gut microbiomes. This episode is broadcasted from Guangzhou, China.

[00:00:39.270] CS

Welcome back. Many drugs are taken on a daily basis and are useful in the treatment of chronic diseases, but what happens when you don’t respond well to these drugs? Is there an alternative to not taking them at all to ensure that you don’t suffer more? A large number of patients do not respond well to commonly used drugs, and some patients even suffer from side effects. In Europe alone, about 3.5% of hospital admissions are related to side effects of medicines.

[00:01:06.930] CS

In this episode I will talk to Professor Fu as a recipient of the ERC Consolidater Grant. Dr. Jingyuan Fu offers a solution to this problem by changing the bacteria that live in the guts of humans. Namely, she researches the idea that we can change our gut bacteria to improve therapeutic outcomes. Professor Fu investigates whether the effectiveness of medicines can be improved by making adjustments to the whole of microorganisms in the gastrointestinal system. Her research is called the Bug Drug Project, and she will focus on 23 drugs used in the treatment of cardiometabolic and psychiatric disorders in her project. We will also speak about her background in academia, the Organ-on-a-chip initiative and the ERC consolidator grant.

[00:01:54.160] CS

Professor Fu, thank you so much for joining me today. So Jing, can you please give us a short introduction? After graduating high school, you attended Nanjing University and then you were a project manager of CAAS or the Chinese Academy of Agricultural Sciences?

[00:02:09.330] Professor Jingyuan Fu

Yes, I worked as an international collaboration officer at the Chinese Academy of Agricultural Sciences, after obtaining my bachelor’s degree in biochemistry at the Nanjing University. I was responsible for bilateral collaboration between China and the European countries. As the Netherlands has advanced agricultural technologies, we had a lot of joint collaborative projects. My work was to stimulate scientific communications and exchanges, organize joint research projects, and provide services to researchers from both countries. This was a very good time in my life. Through this work, I had a good opportunity to know the Netherlands, its culture, society, and the scientific advance. Moreover, it also kept me being aware of all recent development in life science.

[00:03:06.550] CS

Following your job at CAAS and keeping up to date on all the developments happening in the Netherlands, you applied for a scholarship to study at the University of Groningen and pursue a master’s in bioinformatics.

[00:03:20.490] Prof Fu

Yes, it was in 2001 when Wageningen University started to develop the first bachelor’s program in bioinformatics. I realized that it would become a new trend in the 21st century. Thanks to the Netherlands Fellowship Program, I got the opportunity to continue my education in this direction. After obtaining my master’s degree with distinction, I continued my academic journey as a Ph.D. student in the research group of Professor Ritsert Jansen at the University of Groningen. My Ph.D. was about genetic genomics using Arabidopsis, a plant model organism. I developed cutting-edge systems genetics approaches in revealing the molecular pathways from the genotype to phenotype. This led to my cum laude Ph.D. thesis in 2007.

[00:04:20.010] CS

That’s great to hear. And then following this, you joined the genetics department at UMCG and you were working under of Cisca Wijmenga, who is also the current Rector Magnificus of the RUG. And why did you choose to pursue a postdoc in human genetics at the UMCG after your PhD?

[00:04:40.830] Prof Fu

So at that time, the human genome sequence was completed and genotyping technology has become feasible and affordable. With these advanced technologies, human genetics research started to bloom. Through my Ph.D. project, I have built a strong interest in genetics and I believe it is going to be the core of biology. Also at that time, the UMCG launched a very unique LifeLines cohort study. In this study, 167,000 individuals from three Northern provinces of the Netherlands would be followed for thirty years. It would be a great resource to work with. I believe, with my expertise in systems genetics, we can get a better understanding why individuals differ in their risk of developing complex diseases. And my hope was to introduce a new method to improve human health. That was the reason I joined the research group of Professor Cisca Wijmenga and really tried to move to the human genetics field. Actually, she is the pioneer in this area, so I’m very glad to have the opportunity to continue my journey in the human genetics field.

[00:06:03.120] CS

Yes, of course.

[00:06:04.060] CS

That’s very interesting to hear. So let’s move on to your research, the BugDrug research. Can you briefly describe the problem at hand at which you’re the problem you’re trying to solve?

[00:06:17.610] Prof Fu

In medicine, there is no “one size fits all” approach. Each of us is unique in a certain aspect and individual responses to a specific drug vary greatly. We are faced with an urgent need for methods that can distinguish patients with the desired response versus an undesired drug response. Now, we have learned a great deal that our genetics is an important factor. This information has been implemented in optimizing drug choice; this project is called a pharmacogenetics passport project. On the other hand, we have also realized that genetics alone does not give us the full information we need. More importantly, our genetic profile is already determined at conception. It is almost impossible to change our genetics, and the costly new drug development cannot meet the urgent demand for clinical treatment. Therefore, it is of utmost importance to find novel means to enhance the efficiency of already approved drugs and of course, if possible, ways to transform non-responders into responders.

[00:07:38.870] CS

So in lay terms, how would you describe your research?

[00:07:43.220] Prof Fu

My research aims to improve drug efficacy by changing the composition of trillions of bacteria that reside in our gut. Humans can be considered as a superorganism because our body is not only the home for human cells but also the home for trillions of bacterial cells, most of them residing in our gut. We call it the gut microbiome. We already know that microbial composition varies greatly between different individuals. Each composition can contain 100-1000 times more genes than the human genome. Once a drug is administered orally, the unabsorbed drug pass through the upper GI tract and continues into the large intestine. There they encounter those bacteria and then bacterial genes can contribute to drug metabolism, thereby affecting our drug response. So our aim is really to identify the role of bacteria and their enzymes in drug metabolism and seek for approaches to modify them to improve our drug response.

[00:09:02.810] CS

Thank you so much for providing us with that short description of your research. I think especially for the listeners who are not so well versed in the world of gut microbiome, that can really help to just give a short sketch and help us achieve a deeper understanding.

[00:09:18.380] CS

So let’s dive a little deeper into the BugDrug project. And so you have suggested dividing your project into three parts, better predictions, better understanding and a clinical translation. Can you run through the three of them?

[00:09:33.770] Prof Fu

Yes. So in detail, I focus on commonly used drugs in two diseases areas,  cardiometabolic diseases and mental disorders that are major contributors to the public health burden. The first part focuses on better prediction. I will make use of the unique population-based, LifeLines cohort I have just mentioned, where I have detailed information on over 2000 phenotypes for 10,000 individuals, including their genetics, the microbiome, disease, and drug usage. I will identify genetic, microbial, and other factors that underlie the inter-individual differences in drug metabolism and combine them to improve drug response prediction using machine learning algorithms. Part 2 is to focus on a better understanding. I will ascertain a better understanding of host-microbe interactions in drug metabolism. Uniquely for the same cohort. I have also alive gut microbes and human iPS cells available, which allow me to generate a personalized drug testing model that takes an individual’s genetics and the microbiome into account simultaneously. In part 3, I will focus on clinical translation. I will assess to what extent drug efficacy can be improved by manipulating the microbiome using probiotics. This work will be done in collaboration with Professor Iris Sommer from the Psychiatry Department of the UMCG.

[00:11:21.620] CS

You have devided your research into three parts. Can you also tell me a little bit about the different phases and their corresponding timelines?

[00:11:29.240] Prof Fu

Yet the total duration of the project is five years. The part 1 and 2 on human cohort study and the probiotics intervention will take about two to three years, as the sample collection is either completed or already halfway. The part two is the most challenging part. Particularly, we plan to develop a personalized drug testing model which will mimic the bacterial metabolism, drug absorption through the intestine, and further host metabolism in the liver. Therefore, in the first two years, we will focus on technology development. Once the system is ready, we will use it to experimentally validate the findings from the human cohort studies. So this part of the experiment expects to take four to five years.

[00:12:23.900] CS

OK, so have you encountered any difficulties or delays in conducting your research? From the from the sounds of it, you’re continuing with full steam.

[00:12:29.350] Prof Fu

We definitely continue it with full steam. However, we have also prepared ourselves for all possible difficulties and challenges. Luckily, we have set up a strong team and good collaborations in this project. We have a lot of confidence in this project.

[00:12:50.470] CS

Great to hear. And so you mentioned the population study. I’ve got microbiomes, especially of people living in the Netherlands.

[00:12:57.760] CS

Do you have plans to translate this research to China?

[00:13:39.130] Prof Fu

I would be very happy to generalize our findings and to translate this research to China. Actually, I know that many Chinese researchers and institutes have been very actively conducting this type of research. For instance, there was a Guangdong Microbiome Project that has been studying the microbiome in nearly 7000 individuals. Recently, Shenzhen BGI Research launched the “Million Microbiome of the Humans Project” in which we are also a participant. In this project, one million microbial samples from all over the world will be sequenced, including various cohorts from the Netherlands and China. So there will be many collaborative opportunities in the future.

[00:13:51.880] CS

Oh, that’s great to hear this cooperation between the Netherlands and China. Do you think your findings will be similar? Because for me, I can imagine that there are many factors in China which have a larger or smaller effect on a person’s gut microbiome than in the Netherlands. For example, there’s high levels of air pollution. There are different diets. Moreover, there are different diseases and different drugs taken. So do you think your findings will differ:

[00:14:20.890] Prof Fu

That is a very good point. Our studies already showed that each person has a very different microbial composition. It is because we had different genetics, background, lifestyle, dietary habits, and environmental exposures. As you have just mentioned, those factors are pretty different between Dutch and Chinese persons. Therefore, we also expect the gut microbiome will be very different.  Trans-ethnic translation of the microbiome study is a very interesting research topic.

[00:14:57.220] CS

Maybe the next step, the next step in your research. So if your research hypothesis is proved to be correct, we can alter gut bacteria to improve therapeutic outcomes. So do you want to improve drug efficiency by altering gut microbiomes or do you want to adjust drug therapy, or is there a combination of the two you envision?

[00:15:20.740] Prof Fu

Yeah, of course. I think we need to take both into consideration. You know, there is a complex, bidirectional effect between drugs and the microbiome. The microbiome can contribute to drug metabolism. But vice versa drugs can also affect the microbiome. We know that over 20% of non-antibiotic drugs actually have antimicrobial activities. so that we should think of the best therapeutic approaches or the combinations of multiple approaches based on each individual case. That is indeed the concept of personalized medicine.

[00:15:58.030] CS

Yes. So one of the ways in which you suggest altering gut microbiomes is through fecal transplantation. And as a layperson, this sounds very interesting. Can you tell me something more about this?

[00:15:58.660] Prof Fu

There are many different ways to change the microbiome. Fecal transplantation is the method to transfer the fecal bacteria from a healthy donor into a patient. And this approach works well if the whole my gut flora is completely dysfunctional, such as in the patients with C. difficile infection. However, more fine-turning approaches can be developed to target a specific part of our gut microbiome or even a specific strain, such as diet, probiotics, probiotics, and even drugs.

[00:16:50.920] CS

So for a specific type of bacteria target, different specific approaches can be employed. Yes, I can imagine. So another way in which we can alter the gut microbiomes is through organoids on chips. For our listeners who do not know anything about this technology, what can you tell me about it?

[00:17:42.850] Prof Fu

So we know that animal models can fall short in predicting the human drug response. Microfluidic organ-on-a-chip system is an emerging, animal alternative technology. So in this technology, human cells are cultured on chips with very tiny, millimeter-scale channels. Through the channel nutrients and treatment or drugs can be delivered to seeded cells and waste products can be discarded. Amazingly, only under the continuous fluid flow, the cells can form a 3D structure that better recapitulate tissue activity, mechanics, and physiological responses. Another benefit of these systems is that different types of cells can be co-cultured in the chip, allowing cell-cell communications. This technology becomes very powerful when it is combined with human induced pluripotent stem cell technology, by which varying disease tissue types can be generated from one source of patient material. In such a way we can take an individual’s genetic background into account, thereby generating a personalized disease and a drug testing model. For instance, in the current project. We aim to generate intestine-on -a-chip and liver-on-a-chip systems, allowing us to model metabolic flux along the gut-liver axis.

[00:18:51.220] CS

So it’s not only more ethical and that you no longer test on animals and it’s no longer very general because you just test on, you know, random people. But it’s very personalized and very specific to each person and their specific organs and conditions. That’s right. So can you tell me more about the Dutch National Organ-on-a-chip Initiative? So I think your mentor, Cisca, is also a part of this initiative. So what is the aim?

[00:19:22.490] Prof Fu

The Netherlands Organ-on-a-chip Initiative, in short NOCI, is one of the gravitation programs of the NWO, which are funded by the Ministry of Education, Culture and Science of the government of the Netherlands. And the aim of the NOCI project is to develop novel “organ-on-a-chip” technologies, allowing the modeling of disease development and treatment response. The researchers contributing to the NOCI Consortium come from six different universities and institutes which provide very diverse but complementary expertise, such as cell biology, nanotechnology, medicine, genetics, biochemistry, etc, so including our research group from the UMCG. We firstly focus on three types of organ-on-chips, heart, brain, and intestine. In my ERC, I will further develop liver-on-a-chip, which we intend to couple to the intestine-on-a-chip that has been already developed in the context of the NOCI.

[00:20:52.890] CS

OK, so I think you already mentioned it a bit before, but what challenges are there scientifically and technologically in pursuing this NOCI project? Because you’re working with researchers and scientists from so many different fields, it must be a very challenging endeavor.

[00:21:00.010] Prof Fu

And this is indeed a high-risk and high-gain project. When we started we faced a lot of scientific and technological challenges. For instance, each individual chip needs a cell-type-specific architecture to allow tissue-specific cell interactions. Chips need to be designed that integrate relevant electronic sensors. We need to guide the cells towards a physiological 3D architecture and for certain tissues, the IPSC differentiation protocols still need to be developed.

Now, almost halfway of 10 years program of NOCI, we are in the position that we can show that we are met most of the five-year milestones and are perhaps even further than expected. Some of the major hurdles that we will address in the remainder of the program are the development of a new standardized chip format that allows the coupling of  tissue-A-on-a-chip to tissue-B-on-a-chip, thereby taking small steps towards a human-on-a-chip. We then maybe in the future have human-on-a-chip instead of just a single-organ-on-a-chip.  Moreover, we also want to integrate the microbiome in the intestine-on-a-chip that I have mentioned, which actually comes with its own difficulties as well.

[00:22:33.450] CS

Of course. I can imagine that each specific part of the body, each organ has its own challenges and bringing everything together and such a scientific way must be a very complex issue. Yeah. And so you are listed as one of the researchers involved in the project, specifically looking at multidimensional genetics and genomic analysis to understand the development of complex diseases. Very much a mouthful. So what can you tell me about your role in the NOCI project?

[00:23:04.830] Prof Fu

With my expertise in human genetics, informatics, and multi-omics integration, I am involved in omics analysis in multiple projects in the NOCI consortium? Well, I’m also involved in the efforts of integrating the human microbiome in the intestine-on-a-chip to study the host-microbe interactions. In this project, I closely collaborate with Dr. Sebo Withoff, whose team has generated the organ-a-chip platform that I will also use for the gut-liver axis studies. Individually, the intestine and the liver system can also be used to study intestinal and liver diseases, such as celiac disease, inflammatory bowel disease, non-alcoholic fatty liver disease, and bile-transport-related illnesses.

[00:23:55.980] CS

OK. And this is your role in the NOCI project. Does it also fall under your ERC grant or are the two separated from each other?

[00:24:06.980] Prof Fu

They are closely connected. As I have mentioned, I’m a part of the NOCI project. On the other hand, I also have something actually out of the context of the NOCI. For instance, the live-on-a-chip currently is not a part of the NOCI.

[00:24:33.530] CS

So midway through September, HUB organoids and BGI they signed a MOU, which is a memorandum of understanding to further develop Organoid technology. I think you already mentioned BGI in an earlier answer. So as a first question, do you have cooperation with either of these institutes or BGI?

[00:24:59.480] Prof Fu

We do have a collaboration with both Institutes. The Hubrecht Institute and Hubrecht Organoid Technology, are already important partners within NOCI. We also have several collaborations with the BGI, but this is mainly focused on the microbiome characterization in stool samples, such as the “Million Microbiome of Humans Project” that I just mentioned. However, as always, we are very open to set up novel collaborations.

[00:25:31.070] CS

So do you not only want to cooperate with BGI, but also other Chinese universities or institutions or other researchers, or would you prefer to first work on finishing the NOCI project and from then on you start to branch out and go international?

[00:25:51.350] Prof Fu

No, I think we can do this really simultaneously. It is not necessary to only focus on these activities because I think joint efforts can really make the project more successful.

[00:26:02.630] CS

Yes, I think more input from different countries, you know, it can give you new insights. You’re absolutely right. I was also wondering, is this very much an up-and-coming research field to focus on the effects of drugs on your body and how your body and its systems can influence the working of drugs? For example, my colleague has already focus a lot on AMR, antimicrobial resistance. Are we entering a new era of personalized medicine?

[00:26:29.300] Prof Fu

I do think that we are entering the era of personalized medicine and the wealth of medical data has been growing exponentially. Together with individual genetics and genomics information, and with the aid of AI technology, we can now stratify patients for their disease risk and treatment response, so that we can develop customized disease prevention and treatment strategies. The “pharmacogenetics passport” project is an excellent example of how genetic information is implemented in medical care.

[00:27:09.950] CS

Yes, of course I can imagine. And so lastly, working for a Dutch university and you received a European grant. Now you’re working on the Dutch NOCI initiative. To what extent do you still perceive a Chinese connection in your current work? Do you work with Chinese researchers at USCG? Do you keep in contact with Chinese researchers in China?

[00:27:31.700] Prof Fu

There are quite some Chinese researchers at the UMCG and the University of Groningen. We sometimes meet and exchange experiences and thoughts about living and working in the Netherlands. Of course, I also have some contact with Chinese researchers who share the same research interest. For instance, I was invited to give a TED-like talk at the GUT Forum in China in 2019. For my research, I’m very happy and would like to go for the best of science and willing to collaborate with the best researchers all over the world, including those from China as well.

[00:28:07.470] CS

Yeah, yes, of course. No, no discrimination, whether it’s Chinese or Dutch or any other nationality.

[00:28:13.940] CS

Yes. Yes. So let’s take a quick break. And when we come back, we can speak more about the Seagren or the European Research Council Consolidator Granth.

[00:28:27.910] CS

Let’s talk about the ERC. In December of 2020, the attention of the Netherlands Innovation Network fell onto Professor Fu. Namely the NIN was introduced to the winners of the ERC consolidator grants by the Science and Technology Councilor of the EU delegation in Beijing. In 2020, 37% of grants were awarded to female researchers, the highest proportion since the start of the grand scheme. Under the domain of Life sciences, 710 proposals were submitted and 94 were selected, a success rate of 13%in the life sciences domain.

[00:29:02.470] CS

Women won 15 percent and then won 12.9% of these grants as a part of the ERC grant. The grantees will carry out their projects at universities and research centers across Europe. The funding is a part of the EU’s current research and innovation program, Horizon 2020 and work in total €655 million euros. With the support, the new grantees will be able to consolidate their teams and have far reaching impact. Congratulations to this amazing accomplishment of being selected as a recipient of this highly rewarded ERC Grant.

[00:29:37.060] CS

Can you tell us first about the ERC grant? What is it and how did you apply for the grant? Thank you.

[00:29:47.210] Prof Fu

I’m very happy to receive this funding, as this is an extremely excellent source that helps develop your research and improve your independence. The European Research Council grants aim to empower individual researchers and to provide the best setting to foster their creativity. There are three levels of personal grants: Starting, Consolidator, and Advanced grants, depending on the stage of your career. So the consolidator grant is for the researcher who has obtained his/her Ph.D. within seven to 12 years.  I sincerely started to thinking of applying for this grant three years ago. Actually, I tried twice. At the first application, the project was not funded. But I really believed in its potential. So if I have to put my future and my dream into one project, then this is going to be the one. Thank my students, collaborators and colleagues at the Departments of Pediatrics and Genetics, Groningen Medical Center, and also the Netherlands Organ-on-a-chip Initiative, we have generated a lot of preliminary results and obtained  technical advances in the past two years. Therefore, the application became much stronger and more convincing the second time. Of course, this is a very highly competitive grant that requires a lot of preparation. So my a bit of advice to those applying for ERC are: they should start the preparation early and think big because it is really for a big, innovative project; generate some preliminary results to support your hypothesis; of course, it’s also important to ask for help from your colleagues, collaborators, and also from the grant support office of your institute.

[00:31:59.920] CS

Thank you for explaining. So you have received a scholarship to study at Wageningen and now you have received the ERC grant and you are also in the process of applying for the NWO Vici grant. Do you think there is a difference in the funding available for research in China, the Netherlands or in Europe?

[00:32:20.260] Prof Fu

I don’t actually see any big differences in funding availability in different countries. There always are various funding sources at national and international levels. For instance, in the Netherlands, we have the Netherlands Organization of Scientific Research. At the EU level, we have the European Research Council. In China, there is also the National Natural Science Foundation of China. Many institutes can provide different kinds of funding.

[00:32:56.830] CS

So my last question to you would be a very personal one. You are Chinese nationality and you are currently working in Groningen. So that’s my old student and I did my bachelor’s and master’s there. How do you experience the daily life and the Dutch way of working? Of course, you’ve already lived in the Netherlands for twenty years, but something must have attracted you to the Netherlands and kept you there for so long.

[00:33:23.020] Prof Fu

Yeah, Groningen is a very lovely and welcoming city to live in, with all the comforts of city life, but it is close to nature. The size of the city makes it easy to go around and you don’t have that stress that one can experience in a big city, for instance, Rotterdam or Guangdong. Of course, students also constitute a large proportion of the population and we also have over 6000 international students. So the city is alive, full of energy and also with a diverse cultural environment. So I think daily life here is very pleasant. I really enjoy living here. And even in the Corona time, I think the Dutch government, also the local government and the University of Groningen have done excellent work to minimize the impact of the epidemic on individual’s leaving, working, and education. So it is a pretty nice place to live and work.

[00:34:34.100] CS

That’s very good to hear. Well, thank you so much for joining me today and providing us all with your insights. Professor Fu.

[00:34:11.280] Prof. Fu

Thank you. Thanks for this. I’m very happy to have this opportunity.

[00:34:49.280] CS

Thank you, Professor Fu. And thank you for your time. More information on Professor Fu and her research can be found on our Web site, Netherland’s Innovation Network. And here you can also leave your comments. If you would like to reach us, please send an e-mail to [email protected]. I hope you’ll tune in again.

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