New Insights into Cellular Metabolism with Issam Ben-Sahra, PhD

“We thought that PDH (pyruvate dehydrogenase) activity was independent of pyrimidine nucleotides, but we actually now connect PDH activity to pyrimidine metabolism in order to have a functional TCA (tricarboxylic acid) cycle. We think that this is presenting a shift in our understanding of biochemistry. We'll likely actually rewrite the textbook.” — Issam Ben-Sahra, PhD 

• Associate Professor in the Department of Biochemistry and Molecular Genetics
• Member of the Robert H. Lurie Comprehensive Cancer Center
• Member of the Simpson Querrey Institute for Epigenetics

Ben-Sahra’s team is interested in understanding how metabolism is regulated in mammalian cells and specifically how reprogramming can occur in response to environmental changes. 

• Earning his PhD at The University of Nice, Côte d'Azur, Ben-Sahra began his career studying the impact of metformin on cancer cell viability. He then completed his postdoc at Harvard University where he proved that the protein mTOR is a driver of nucleotide synthesis. 
• In a recent paper published in Science, Ben-Sahra identified that the nucleotide called pyrimidine can be used as a phosphate donor to allow metabolic metabolism to work. Pyrimidines are one of two types of nucleotides in the body.  
• Additionally, Ben-Sahra discovered that pyrimidines can be used to activate vitamin B1, where they are used for metabolic processes in mitochondria to support central carbon metabolism. 
• Most notably, it was discovered that this activation of vitamin B1 impacts the enzyme pyruvate dehydrogenase (PDH), and through its connection to the production of citrate, directly influences adipogenesis (the formation of fat cells). 
• This study has significant implications in the study of obesity and other metabolic diseases and represents a potentially major shift in the understanding of biochemistry.  
• Pyrimidine nucleotide synthesis inhibitors are now in clinical trials for cancer. It’s possible that these inhibitors, if taken in excess, could result in vitamin B1 deficiency.  
• It’s also possible that targeting vitamin B1 metabolism by targeting pyrimidine synthesis could be a way to study the possibility of preventing diet-induced obesity. 
• Ben-Sahra argues how crucial it is to fund basic science research. Without a comprehensive understanding of molecular mechanisms prior to translational research, therapeutic products could potentially enter the market that are detrimental to health.  
• For Ben-Sahra, simplicity is the ultimate sophistication in science. Furthermore, investigators should aim to “kill their hypothesis” rather than prove it.  
• Presently, Ben-Sahra and his lab are trying to connect signaling pathways and metabolism, specifically trying to find a new metabolic pathway that is regulated by a signaling network. They are also trying to locate a new metabolite that could be involved in regulation of several biological processes.

Recorded on September 16, 2024. 

Additional Reading 

• Read Ben-Sahra's recent study in Science.
• Learn more in a review paper Ben-Sahra co-wrote for Trends in Cell Biology.
• Watch a video about the Ben-Sahra lab.

Target Audience

Academic/Research, Multiple specialties

Learning Objectives

At the conclusion of this activity, participants will be able to:

1. Identify the research interests and initiatives of Feinberg faculty.
2. Discuss new updates in clinical and translational research.

Accreditation Statement

The Northwestern University Feinberg School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Credit Designation Statement

The Northwestern University Feinberg School of Medicine designates this Enduring Material for a maximum of 0.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

American Board of Surgery Continuous Certification Program

Successful completion of this CME activity enables the learner to earn credit toward the CME requirement(s) of the American Board of Surgery’s Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit.

Disclosure Statement

Issam Ben-Sahra, PhD has nothing to disclose. Course director, Robert Rosa, MD, has nothing to disclose. Planning committee member, Erin Spain, has nothing to disclose. FSM’s CME Leadership, Review Committee, and Staff have no relevant financial relationships with ineligible companies to disclose.

All the relevant financial relationships for these individuals have been mitigated.

[00:00:00] Erin Spain, MS: This is Breakthroughs, a podcast from Northwestern University Feinberg School of Medicine. I'm Erin Spain, host of the show. Today we're talking about Northwestern Medicine research that could rewrite textbooks on our understanding of cellular metabolism, and provide potential new targets for cancer and metabolic diseases such as obesity. This research comes from the lab of Dr. Issam Ben-Sahra, an associate professor in the Department of Biochemistry and Molecular Genetics at Northwestern University Feinberg School of Medicine and a member of the Robert H. Lurie Comprehensive Cancer Center. His team has discovered how cellular metabolism fluctuates in response to changes in levels of pyrimidines, metabolites used by cells to make DNA and RNA. The discovery published in the journal Science has been praised for its rigorous simplicity and underscores the importance of understanding the molecular mechanisms that underlie specific biological processes. Welcome to the show Dr. Ben-Sahra.  

[00:01:13] Issam Ben-Sahra: Thank you. Thank you for having me.  

[00:01:14] Erin Spain, MS: Absolutely. Give our listeners an introduction to the research that you're doing here at Northwestern. 

[00:01:20] Issam Ben-Sahra: We are very interested in understanding how metabolism is regulated in mammalian cells. The metabolic pathways have been charted for years in our biochemistry textbooks. So in the textbook, we know very well all the pathways. But we don't really know how metabolism responds to change in the environment and also to, for example, oncogenic drivers. So in cancer, for example, when you have oncogenes, or loss of tumor suppressors, metabolism can be reprogrammed. And my lab has been really interested in understanding how this reprogramming occurs in response to these changes. 

[00:01:56] Erin Spain, MS: I'd like to hear a little bit more about you and your journey into science. So if you could just take me back a little bit. Tell me what got you into the field and what brought you to Northwestern specifically to study cancer? 

[00:02:08] Issam Ben-Sahra: I did my PhD in France. I'm French. I'm from Nice. So I did my PhD at University Nice, Côte d'Azur. I studied metabolism when I was a PhD student where I was really focused on the drug that was used for diabetes. This drug is called metformin. Metformin is taken by hundreds of millions of people in the world. But my PhD work was to understand the impact of metformin on cancer cell viability. And we found that metformin surprisingly had a very potent effect on cancer cell growth in vivo and in vitro. So that was my PhD work. So it was at the time quite surprising. Now there's more paper about metformin in cancer. But at the time it was kind of surprising that anti-diabetic drugs could have an effect on cancer cell viability. And from there I moved to Boston, where I did a postdoc at Harvard University under the guidance of Dr. Brendan Manning, where we are focused on the protein called mTOR. So mTOR is the mechanistic target of rapamycin. This protein is a key regulator of metabolism. What it does, it controls the balance between anabolism and catabolism, and is a regulator of glycolysis, protein synthesis, lipid synthesis. And we showed during my postdoc that mTOR drives nucleotide synthesis. And from there, this is where I fell in love with nucleotide synthesis. And this is where I keep working on nucleotide metabolism in my own lab. So it started from regulation of metabolism by metformin to regulation of nucleotide metabolism by mTOR signaling. And now we're studying nucleotide synthesis in a broad context as well. We still have projects on mTOR signaling as well in the lab.  

[00:03:47] Erin Spain, MS: So the metabolism of cancer cells operates differently than normal cells. And those in this field know that this difference was first discovered by German physiologist, Dr. Otto Warburg in the middle of the last century. So give us a quick history lesson here. Explain what Warburg discovered and how that applies to the work you're doing today.  

[00:04:06] Issam Ben-Sahra: In the 1920s Otto Warburg identified that cancer cells have a different metabolism than normal cells. And he showed that basically cancer cells reprogram their metabolism to make more lactate, which was known to be a byproduct or a waste product glycolysis and lactate is secreted in the environment. And he thought that basically cancer cells were behaving like yeast cells. They were actually fermenting glucose. They were using glucose and making lactate. They were doing fermentation even in the presence of oxygen. So he thought that basically mitochondrial metabolism was completely down or down-regulated in cancer cells. But we know now it's not the case. Cancer cells have actually operating mitochondria. They also have higher glycolysis, but that observation was not completely right. But really his observation really put the focus on metabolism of cancer cells, and now we have shown that, there's so many things happening in the metabolism of cancer cells that are worth studying. 

[00:05:10] Erin Spain, MS: So now here we are more than a hundred years after Warburg's discoveries. And you've published a paper in Science where you report some surprising discoveries about the role of metabolites in cellular metabolism. Tell me about this study and what you found. 

[00:05:25] Issam Ben-Sahra: We have two types of nucleotides in our body. We have purines and pyrimidines. And since the 1940s, ATP, adenosine triphosphate, which is known as the energy currency of the cell, has been known to be used as a phosphate donor for all the metabolic reactions that happen in our body. So there was like this big dogma that ATP is the major phosphate donor. But in this study published in Science, we identified that another nucleotide, pyrimidine nucleotide, called UTP, or uridine triphosphate, this nucleotide can be used as a phosphate donor too, to allow metabolic metabolism to work. So, we know now that ATP is not the only phosphate donor that happens in the cell, but UTP could be used as a phosphate donor as well. And basically in this paper, we uncovered that UTP, this metabolite, can be used to activate vitamin B1. So vitamin B1 is an essential vitamin. Many types of food have vitamin B1. You can find vitamin B1 in nuts, in types of meats, in different types of fruits as well. So we need to consume vitamin B1 daily, but in order to have vitamin B1 to work in our body, we need to activate that vitamin B1, and that happens through this metabolite UTP. UTP allows the activation of vitamin B1. Once this vitamin B1 is activated, that means it's phosphorylated, vitamin B1 will be used for metabolic processes in the mitochondria to support basically central carbon metabolism and basically anabolic metabolism, lipid synthesis, etc. Basically we uncovered that UTP donates a phosphate molecule to charge vitamin B1 into an active form of vitamin B1 called TPP or thiamine pyrophosphate. So thiamine pyrophosphate participates in several biochemical reactions in the mitochondria to support the Krebs cycle, also called TCA cycle. The Krebs cycle is required to support the electron transport chain and the mitochondria, the extensive phosphorylation, but also required to make citrate, and citrate is a key precursor for lipid synthesis. So you need citrate as a metabolite to support lipid metabolism or lipid synthesis. So why do we care about lipid synthesis? Because lipid synthesis are required to make fat. You know, fat is actually coming from lipid metabolism. And we show in this paper that this regulation of basically vitamin B1 metabolism leads to the regulation of an enzyme called PDH or pyruvate hydrogenase. That enzyme is required to make citrate. And we show that basically this metabolite that citrate is required for lipid synthesis, allowing basically more fat to be made and allowing adipogenesis, adipocyte differentiation, and therefore we think that this new mechanism could be used to study obesity and to study other metabolic disorders as well. So we think that this is actually an important finding because so far we thought that PDH activity was independent of pyrimidine nucleotides, but we actually now connect PDH activity to pyrimidine metabolism in order to have a functional TCA cycle. We think that this is presenting a shift in our understanding of biochemistry. We'll likely actually rewrite the textbook. 

[00:08:46] Erin Spain, MS: What about potential therapeutic applications that might exist to target this and for both cancer and maybe other health issues, metabolic disease, or as you just mentioned, obesity as well. 

[00:08:56] Issam Ben-Sahra: It's a great point. Pyrimidine nucleotide synthesis inhibitors are now in the clinical trials for cancer. So it'd be interesting to see what happens to these people taking these inhibitors, what happens to this mechanism we identified. It's also important to understand whether this patient could have vitamin B1 deficiency because if they take too much of these inhibitors, you might affect the ability of vitamin B1 to be activated and therefore they might have a vitamin B1 deficiency. They might need to take supplements of vitamin B1. But we think also that this mechanism could be exploited in context of metabolic disorders because targeting vitamin B1 metabolism, with this mechanism targeting pyrimidine synthesis, could be a way for us to study whether we can prevent diet induced obesity such as you know, Western diets, which is heavy in carbohydrate and fat. And it would be interesting to see whether we can, by targeting pyrimidine synthesis, we can prevent weight gain induced by this diet. So we are exploring that in mice now to see whether we can prevent that. And then eventually study whether this can be applicable to patients. 

[00:10:07] Erin Spain, MS: Could there be a message here, for example, food manufacturers and just consumers who are looking to get more vitamins into their diet, why they might need to be cautious.  

[00:10:18] Issam Ben-Sahra: I think in the food we have a lot of vitamins. Sometimes in some food, they have this called fortification of vitamins. So they add a lot of vitamins. And this happens, for example, in some cereals. They add extra amounts of vitamins, especially vitamin B1, which is the vitamin that we're studying here. And people think vitamins are good, but too many vitamins cannot be that good because if you give too much vitamin B1 in that fortification of food, you might actually lead to increased obesity and increase in adipocyte differentiation, so therefore increasing obesity and fat. It's important to understand that basically our study reveals these kinds of flaws that too much vitamin B1 could be actually detrimental for health. 

[00:11:03] Erin Spain, MS: And while are always interested in knowing when there might be human clinical trials coming, it's important to know this is basic science research. And can you talk a little bit about that and the importance of really understanding the molecular mechanisms behind specific biological processes and why that's so important.  

[00:11:23] Issam Ben-Sahra: So we need really to understand the mechanisms before going into translational research. And I think funding basic science, fundamental research, is the key for improving mankind's health and mankind's knowledge. So it's very important that basic science has to be funded in order to advance our knowledge and then find treatments later. Now in our days, we have a lot of big data science. And I see a lot of papers about big data science. We have so many information on the data. We have a lot of information on biology, but we don't really dive into the mechanisms that underlie those changes. And I just hope that biologists will dive more into the molecular mechanisms instead of just presenting information science or data science, and use that data science to really come up with clear hypotheses that we can actually use to solve a biological process or find a new mechanism driving specific biological processes in order to eventually find a cure or a therapeutic strategy to help people with disease. So this is very important to me that basically I think the grant agencies tend to favor this big data science, and think that what we do is too simple or too reductionist. But actually, it's also very important to understand in the reductionist level, the molecular mechanisms. Because without molecular mechanisms, we can sell products that can be doing things that are supposed to do, but with a mechanism that we don't know and might end up having some detrimental effect. 

Erin Spain, MS: Because there is this race out there right now to end obesity, to end cancer. There's new drugs hitting the market all the time, and we hope that the science is there. 

[00:13:09] Issam Ben-Sahra: Exactly. we need to be careful. And I think as a scientist, we have very rigorous randomized clinical trials before moving into the market, that's for sure. So in this context with this paper, we think that we are going to find what we see in mice. If we see that we have promising results in mice, we will go forward and maybe think about finding a way we can target pyrimidine synthesis in obesity and different types of patients.  

[00:13:37] Erin Spain, MS: Talk about the reaction from the community once this paper was released. I know you posted about it on Twitter and you got some interactions there, but what has the scientific community said and what have you heard as far as feedback from this paper?  

[00:13:50] Issam Ben-Sahra: I think people are very excited about this paper. I've received very good feedback from the paper. People really appreciate the work, the mechanistic aspect of the work. I got praise that people say it's a rigorous work and also very simple as well. It's a simple study. And I think for me, simplicity is the ultimate sophistication. For me, it takes a lot of hard work to make something simple, to truly understand underlying challenges and basically come up with elegant solutions. So, I think it's something that really I try to push people to dive into the really molecular details to really understand the mechanisms and to make the story as simple as possible because it's always challenging when you have convoluted different type of research.  

Erin Spain, MS: Where did that come from, that drive to make things, like you said, simple but elegant and not leaving any stone unturned? Tell me about that philosophy. Where does that come from? 

[00:14:42] Issam Ben-Sahra: I think this philosophy really comes from my postdoc advisor. We really think about this aspect that less is more sometimes. So, you don't want to overwhelm the people by too much data. You want to really understand the ultimate mechanism that you're proposing, but going really deep as much as you can to understand that this mechanism is correct or not. And we really try in the lab to really come up with the experiment that will kill your project. I don't see a science as like you have a hypothesis and you need to validate the hypothesis. Our goal is to really try to kill your hypothesis with experiments. And at the end, if you cannot kill your hypothesis, you might be right. It's never a hundred percent, but you might be right. And then you can go ahead and publish it. And then in the future, we'll see if this holds, but this is important for us to really try to be correct and try to be simple, reductionist, but also very mechanistic.  

[00:15:37] Erin Spain, MS: Tell me about the environment at Northwestern and the resources and the team that really made this discovery possible. 

[00:15:44] Issam Ben-Sahra: We have great resources at Northwestern. We have a Metabolomics Core at Northwestern that is driven by Dr. Peng Gao and directed by Navdeep Chandel, who also is the Faculty Director of the Core. So we're very grateful for our collaborators at Northwestern. We have collaborated with Ali Shilatifard as well who is a strong collaborator and he's our chair of the department here and really helped us to move forward this project. So this project was driven by two postdocs in the lab where they're both co-first authors. So Dr. Umakant Sahu and Dr. Elodie Villa. They have pushed forward this project and it was really fun to dive into the mechanisms involved in this regulation. We have also collaborators in Boston as well. John Asara, who is also doing a lot of mass spectrometry-based experiments for us. 

[00:16:31] Erin Spain, MS: Tell me what other projects are taking place in your lab right now and what can we expect to see in the coming months and years? 

[00:16:38] Issam Ben-Sahra: So we have different projects that are going on in the lab. We are trying to connect signaling pathways and metabolism, and we're doing this in an unbiased way. So, you know, there are several signaling pathways that are known to regulate several biological processes, but they haven't been linked to metabolism. And our goal is to identify whether we can link these new signaling pathways to metabolism. So we're doing a lot of screens now, trying to find new metabolic pathway that is regulated by signaling network. We also, as I said, we're developing this field of metabolic signaling, trying to find a new metabolite that could be involved in regulation of several biological processes. We have a project ongoing now that links 16 eight availability to change in nucleotide synthesis. So we are working in that as well. 

[00:17:24] Erin Spain, MS: Thank you for coming on the show. I really appreciate your insight today and wish you luck on all of your future projects. 

[00:17:31] Issam Ben-Sahra: Thank you, Erin. I appreciate it. Thank you very much. 

[00:17:33] Erin Spain, MS: Thanks for listening, and be sure to subscribe to this show on Apple Podcasts or wherever you listen to podcasts, and rate and review us also for medical professionals. This episode of Breakthroughs is available for CME Credit. Go to our website, Feinberg.Northwestern.Edu, and search CME.