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Let me explain the title, first! Apparently, the first time this has shown up in the academic literature was in 2003 (ref), when Anderson et al, 2003 was investigating the reason why US health expenditure was much higher than Europe and the conclusion was written in a provoking title saying: It’s the price, stupid (by the way, in 2019 they published yet another paper claiming the same thing (here).

In 2016, Anthony Davies, founder and CEO of Dark Horse Consulting, adapted this phrase to “It’s the CMC*, stupid” (ref), making reference to the fact that in the prestigious JPM meeting of 2016, companies were aware that manufacturing challenges were likely the most relevant problem to be solved in order to bring cell and gene therapies to market and enable curative treatments to reach patients.

Recently, at a panel discussion the last ASGCT 2022 meeting in Washington, DC the table coordinator improved on that even more and said: “It’s the COGs*, stupid!”, which I unceremoniously stole as my running title.

If you attend one of these cell and gene therapies meeting you will quickly realize that manufacturing is the big elephant in the room to be addressed and the question becomes: how to develop therapies that can be used for potentially hundreds of thousands of patients, if efficacious?

There is no consensus on what we need to do to have a trully scalable cell therapy, but we can borrow from another industry to understand what the main problems are related to scaling cell manufacturing: cultivated meat. In the cultivated meat space, it is known that culture media, the nutritious liquid used to cultivate cells outside of the body (equivalent to blood in the body) represents up to 80% of all costs (ref) and this is a main point in the end of the day. We can say that allogeneic therapies (those in which one product will be used for many patients) will face similar challenges to cultivated meat and therefore we can anticipate that the only reagent scaling linearly in the process is media. That is just another way to say that media will increase in volume as scales increases in size (seems obvious but needs to be said). As it turns out, cell culture media is prohibitively expensive costing north of $500/L (lowest estimates) and up to $2000L in some cases.

If we truly want to tackle this challenge of scalable cell therapies, we need to critically face this problem of current media cost. Therefore, the first step forward is to be able to rethink the entire media composition from the ground up. At LizarBio we have developed negligible-cost cultivation iPSC media that is 100x less expensive than current alternatives (here) costing less than $5/L. Now, for the first time in history, we can fully commit to large scale suspension-based cultivation systems without incurring in huge media costs.

We understand that cultivation of iPSCs is just half of what we need to do. After cultivating these cells, we need to differentiate them into specific cell types, that will themselves be used as therapies. We are also working on this. As an example, we are quickly approaching a milestone in which we produce 1 billion fresh heart cells for as low as $50. Since we don’t have a media bottleneck regarding suspension culture systems anymore, we can now fully commit to suspension-based scalable therapies. We believe, this has the potential to change the landscape of cell therapies worldwide, potentially making curative cell therapies mainstream.

We know that each cell type will require its own set of process and nutrients to be cultivated. Therefore, the path to build a platform to produce any cell type in the body encompass more than what we have laid out here do far. Stay tuned for more information that will be shared about this.

As always, we keep pushing!

*if you are new to the field COGs stands for Cost of Goods and CMC stands for Chemistry, Manufacturing and Controls (part of a new pharmaceutical product application to the US Food and Drug Administration),

Previously, we have discussed here that cell therapies hold great promisses but are currently limited in their potential by manufacturing problems, that is, even successful (read approved) cell therapies are only treating thousands of patients a year, not millions. Think about this: as of today, there are many patients that could potentially be treated by an approved game changing curative cell therapy but they cannot access it because the manufacturer has no means to actually produce and deliver that therapy for all patients. Whenever a process cannot reach the volume we need it to reach we say that the process is not scalable.

You might think: why would a drug/cell therapy manufacturer develop an unscalable process? This is a great question that begs for a more in-depth answer.

Let’s just get the perspective of small molecules here as a therapeutic product. Whenever you found a new molecule, you found an entity that can be protected (patented) and there might be many routes of chemical synthesis to produce it. Regardless of the route of synthesis, if you end up with that molecule, you have the same product. After all, this new entity is chemically defined.

Now when working with biologics (proteins or cells) that is not the case at all. It turns out that the process with which you produce your biological product defines your product. So if you make changes to your process, you are very likely to change your product too. This reality gave birth to what is generally assumed to be a truth statement in the CMC space for biologics: the manufacturing process IS the product.

Now let’s go back to the previous question: why would a therapeutic company develop a non-scalable process to produce a cell therapy product? Because to develop a scalable solution, the company needs to spend millions of dollars in process development to make sure their processes are scalable even BEFORE they try their products in clinical trials. This means, if their product fails in clinical trials, they would have spent large sums of money that can’t be recovered now. So, to avoid this, these companies generally tend to disregard how expensive or complex (read unscalable) their manufacturing process really is in order to advance their clinical programs and get true human data (which is the most important piece of info a therapeutic company really needs). You can probably guess the results by now: many companies do fail indeed (the odds of success are small) but the ones that do succeed, are now bound to their unscalable high-cost manufacturing process that can only be deployed for very small patient population (and very high price tags). Even if they wanted to change their manufacturing process, they wouldn’t be able without needing to shoulder the costs for another clinical trial to prove their therapy remains effective in despite of the changes they made in their manufacturing process. After all, the process is the product. If you change the process, you very likely changed the product too. They fell prey for the manufacturing trap.

Don’t get me wrong: the company owning the successful therapy will very likely and justifiably reap the benefits of developing such a successful therapy. Patients too will benefit. However, just a small portion of them. This is the upsetting part.

In order to break that cycle, we need to think on scalable process from the beginning. The only answer we need to answer prior to this is: do we really believe cell therapies will have a prominent role in the future? If no, then we don’t have a pressing need. If yes, than it is safe to assume we should be working on scalability of these therapies ASAP. At LizarBio the answer for us is a loud YES and therefore we are building the first platform to produce any cell type in the body at industrial scale for therapeutic applications fro 1% of the cost. We hope that in the future, no patient will be underserved because of manufacturing constraints. Stick around to know more on how are doing this.


Here is an interesting fact: you are made of roughly 37.2 trillion of cells (Ref) (yes, there is a paper about it on the web1). This means that you can be basically reduced to 37.2 trilllion functional autonomous parts that work very well in synchrony. This is beautiful! However, there is more we can apprehend from this like the fact that there are diseases that arise because some cells are either lacking or malfunctioning. This is an important information with potential interventional consequences. Think about diabetes type 1 for example: more than 20m people have type 1 diabetes in the world because somehow their body destroyed (auto immune disease) their insulin producing cells. All the rest 37,18 trillion cells are likely alright, but those 2-3 billion insulin-producing cells got cleared and this patient now has a lifelong problem. The same case could be made parkinsons, multiple sclerosis, heart failure, etc. There are many diseases that could potentially be curative if we could produce these cells.

And here comes science again: up until 2007 we didn’t have a technology to ethically produce unlimited amounts of human cells in the lab. Thanks to a Japanese group of scientists2 we now can cultivate an ethically source of cells that give rise to potentially any cell type in the body. This fundamentally changes our perspective on regenerative medicine.

After this breakthrough, there comes a time for more innovation. Researchers generally work with miniscule number of cells (think thousands to millions – this is almost invisible to the naked eye) in controlled environments to learn more about their biology. However, for regenerative applications to really take off, diseases like diabetes will need to dose hundreds of millions to billions of cells per patient. Now think with me for a second: imagine we can produce the right cell type for diabetes (Vertex is heading the pack and you can read more here) and you can prove beyond reasonable doubt the therapy works. How many of the 20 million patients will be able to get treatment? By following suit to what current successful cell therapies do today, you can estimate about 1000 patients a year. So, think about this: even if a curative therapy is developed and is successful, current manufacturing process could restrict patient access to less than 1% of patient population. That’s a huge problem, right? LizarBio Tx believes so and we are tackling it head on! We will dive deeper in future posts! Stick around!


  1. Bianconi, E. et al. An estimation of the number of cells in the human body. Ann Hum Biol 40, 463–471 (2013).
  2. Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–72 (2007).

We have come a long way since American embryologist Ross Granville Harrison developed the first techniques for cultivating living cells in vitro back in 19071. Since then, we have learned a lot from many experiments and scientist that layed out the foundation for cultivating cells in vitro and understanding key concepts associated with behavior of cells. One very interesting case (that can also be read in the ref below) is regarding Nobel-prize winner Alexis Carrel. In his early work with chick embryo heart, Dr Carrel postulated that cells could grow indefinitely if cultivated in the right conditions (this particular cell line was cultivated for amazing 34 years, continually). However, later work done by other scientists including Leonard Hayflick states that, the regular aging mechanisms of a cell will allow it to only divide between 40-60 times before entering what we now call senescence which is a state in which cells no longer divide and then initiate cellular breakdown processes known as programmed cell death2 (several hypothesis remain to explain Carrel’s work, including accidental seeding of new cells or transformation). However, there are cell types that can overcome such growth limits such as pluripotent stem cells and cancer cells and can be grown virtually indefinitely. The most famous case for this is the HeLa cell line, which has been around since 1951 and is still used today (more on this link -

In a very simplified version of what cultivating cells in the lab means, we can say that the same way cells in the living organism is autonomous but require blood and oxygen to survive, the lab grown cells face the same restrictions but instead of blood, they are fed with a liquid medium that carry all the nutrients (several media are available for different cell types) and researchers need to change that media every once in a while (daily sometimes) in what is still a very manual process.

Text Box: Fig 1: Researcher changing media. Cells are attached to the botton of the plastic plate and are not visible to the naked eye (Source

There are many applications for cultivating cells in vitro. The main ones are: running experiments and diagnostic assays, producing pharmaceuticals and vaccines and, most recently, developing therapies and cultivated meat. The first two suggestions are accomplished in relatively small scale (think thousands to millions of cells/batch). However, as we move towards the latter ones, we begin to think of billions to trillions of cells/batch. Just think that in a human heart you find about 20m heart cells/gram of tissue3. If you want 100g beef, you would be looking into something like 2b cells/piece. Now multiply that by how many 100g beefs do you eat per month, and you will get what a regular single client would consume in a month! Definitely, this is a LOT of cells. The same goes to realize the promise of regenerative medicine and creating organs in the lab.

This why there is still room for many technologies to be developed that help us cultivate these cells at industrial scale and be able to take on important challenges for our society (health and food). LizarBio is directly involved on this by developing and using media that are negligible cost4 to cultivate the cells used in our process to generate curative therapies for patients with incurable diseases. We understand this is an important step towards the fulfillment of the benefits of cellular therapies in the world.


  1. Jedrzejczak-Silicka, M. New Insights into Cell Culture Technology. (2017) doi:10.5772/66905.
  2. Hayflick, Leonard. "The limited in vitro lifetime of human diploid cell strains." Experimental Cell Research 37 (1965): 614–36.
  3. Laflamme, M. A. & Murry, C. E. Heart regeneration. Nature 473, 326–35 (2011).
  4. Kuo, H.-H. et al. Negligible-Cost and Weekend-Free Chemically Defined Human iPSC Culture. Stem Cell Rep 14, 256–270 (2020).

Last week we shared a small but meaning thing that shows how much work is necessary to produce 1 billion human heart cells. This is a significant number because estimations by some researchers (doi:10.1038/nature10147) have pointed to 1 billion heart cells being number of cells that could potentially have a meaningful impact in patients with ischemic heart failure.

We have been advocating for a need of industrial scale processes to cultivate and differentiate human cells because we Do NOT see a future in which producing human cells at industrial scale is NOT in it. I doesn’t matter how different we look into the future, it seems very unlikely that we will not have mastered human cell cultivation and differentiation in industrial scale somehow. We think it will become something like producing recombinant protein today. You would be hard pressed to find a relevant pharmaceutical company not developing a product using recombinant protein technology. Cell therapy will become mainstream and LizarBio is working on this problem today.

Source: Reptile8488/Getty Images

I want to do some simple math to show the problem the industry face today in manufacturing and why scaling manufacturing processes are relevant.

Treating 1% of a patient population should not be our end goal, but this gives us a little perspective on where we should aim and the size of the scalability problem. And this rationale also works for other diseases such as diabetes, muscle wasting diseases and others. There are game changing medicines being approved with curative potential (just like Novartis Kymriah) that are so expensive and complex that over 5 years have been able to treat only about 5k patients worldwide ( So are plenty of patients in need of a curative treatment.

Therefore, why people don’t scale their current manufacturing process? This is key point: in biotech, the process IS the product. Therefore, once settled for your manufacturing, it will be very challenging to change it later on (specially if it is working fine). Therefore, companies tend to sacrifice scale, in order to obtain a small, but sure revenue stream. Hardly a bad economic decision. However, we are then left with high end therapies that can benefit only a small number of patients.

LizarBio is working to democratize cell therapy and be able to help as many patients as possible.

We keep pushing!

#celltherapy #ipsc #heart #regeneration #stemcells #biotechnology #industrialscale #innovation #biology #startup #biotech

In the general public, there is a sense that there only exist 2 general cell types: regular cells and stem cells. This is somewhat correct but it doesn’t capture the true complexity of what actually exist. By regular cells we generally mean “fully differentiated cells” and this refers to cells that have reached their end stage and will no longer give rise to any other cell type. Eventually, this cell will senesce and die. As for stem cells, there are many ways we could categorize them, nevertheless, for simplicity sake, we will say we can have 3 categories of stem cells differing in their level of potency: Totipotent, Pluripotent and Multipotent.

Ref of image:

Totipotency is a very peculiar level of stemness and only found in very early-stage, right after sperm fertilizes the egg turning into a zygote and remaining through the first mitosis after that. This stage is very unique because a totipotent cell is actually capable of giving rise to entire human beings including embryonic annexes such as the placenta. This is exactly how identical twins come into being. Cells that are totipotent in nature get separated somehow in the uterus and develop independently of one another. Cool, right?

Second stage is the pluripotent stage. At this stage cells from the zygote have divided more and began a process in which they lose part of their capacity to differentiate into any cell type and give rise to different types of stem cells with a lesser differentiation potential (this process is called differentiation). Pluripotent cells are present in the blastocyst (a development stage) and these cells have the potential to give rise to all the cell types in the body, except the embryonic annexes. So Pluripotent stem cells are derived from Totipotent Stem Cells that differentiated and now have lost some of their stemness. Both Pluripotent and Totipotent have only been found in embryo stages and not in the fully developed individual. Embryonic Stem Cells and induced pluripotent stem cells are both types of pluripotent stem cells that can be cultivated in vitro.

Finally, Multipotent Stem Cells are cells that can give rise to other cell types but with limited potential (maybe two or three cell types). These cells are found in newborn and adult tissues and serve as a reservoir of cells or replace damaged or aged tissue.

Currently there has been a surge on the number of clinical trials using pluripotent stem cells as a source for obtaining highly pure and differentiated progeny because, if successfully cultivated and differentiated, pluripotent stem cells can become a platform for the development of future therapies.

LizarBio works exactly to bring this reality to patients and help cure incurable diseases by industrially producing these cells in the lab and making them available to patients.

Stick around for more info in the future.

Last post we made brief intro on the uniqueness of developing a biotech business in a mostly tech flooded world where most metrics and KPIs generally used do not apply. Well, then, what should apply? How should we evaluate progress on of a biotech? Again, remember we are mostly focused here on the concept of therapeutics, biotherapeutics and advanced therapy medicinal products (ATMPs – mostly cell and gene therapies) but the framework could be cautiously extrapolated to related fields as well.

In a tech drive world, revenue is a very relevant metric as it speaks quite directly to the acceptance of the costumer to your product to the point of paying for it and recurrent revenue speaks to how loyal these costumers are to your solution. As you know, a biotech can’t sell until regulators approve its product. Therefore, generally speaking, approval by regulators serves as a proxy for a successful product meaning that if you can convince regulators that your product works, you will have a market to tap into (there are relevant considerations to be made here, but this will be for later posts). Now, the question becomes: how to get approval from regulators about the efficacy and safety of your product and how this relates to risk? Historically, this has been roughly divided in 4 stages (before approval), but I will add an extra one in the beginning to explain investors rationale from a startup perspective.

According to the handmade lines in figure 1 you will see the four stages, namely: preclinical, Clinical trials phase 1, phase 2, phase 3 and I will add the proof-of-concept (PoC) before the preclinical stage. Notice that as the stage of the product towards approval progresses in time the perceived risk diminishes (inverse correlation). This seems like a straight-forward model to evaluate risk and it is. Now we will share some insights on what to expect on each stage.

On the first stage (PoC) the company is laying out its foundations filling (or licensing) patents and building a strong case for its business. Scientifically, the company is running the most fundamental of its experiments to prove beyond reasonable doubt that its tech works and this very likely involve key animal experiments in the most translational model accepted in the literature. Likely the results would need to be published (after being file for patent when relevant) and this generates reliance to the general public and investors that you have a somewhat solid case for your business. Generally, the company is taking high risk capital (pre-seed/seed capital) and relying heavily on grants. Some cases the company is still inside universities, sharing a room with other companies somewhere or at incubators on stealth mode. Larger venture firms (like Arch Ventures, Flagship Pioneering, Atlas Ventures, etc) create their own companies internally at this stage and no one knows about them. It is harder to find investors at this point and negotiations need to be kept simple (SAFEs from Y Combinator are a good benchmark) because, in the end, there will be much more to come. Investment sizes vary immensely but I would say anything adding up to US$10MM could be considered a seed round and do not expect one single check but rather many small checks ~US$200-1M) until your point has been made clear. There are cases of large seed rounds (>US$10MM) but these are the exception, not the rule.

Next time, we will take a deeper look into the Preclinical stage and what to expect. Stick around! 🙂

In the last scientific post, we recapitulated a bit of the history behind the, arguably, the most successful and widespread stem cell treatment out there which is hematopoietic stem cell (HSCs) transplant (more commonly known as bone marrow transplant). In this treatment, the goal is to replenish the entire repertoire of blood cells in a patient. Today we will focus on another adult stem cell population that have gained much public attention and was initially described as a sub-set of the stem cells found in the bone marrow: the Mesenchymal Stromal Cells (MSCs).

Some technical background: it has been known for a while that HSCs are cells that grow in suspension in vitro, that is to say they don’t need any anchoring to grow, but rather they divide and multiply without being in contact with any surface. However, a Russian researcher called Alexander Friedstein in the 60s and 70s described a population of cells that, contrary to HSCs, appeared not to grow in suspension, but attached to the bottom of the plastic plates1. After a series of studies and further contributions by American scientist Arnold Caplan, the scientific community began hypothesizing if these cells could be the ones that give rise to all tissues derived from the so called “Mesenchyme” which would be blood, muscle, bone, blood vessels, etc2. After 1999, many groups started describing these cells in all sort of tissues of the body (bone marrow, adipose tissue, muscle, liver, brain, etc) and suspecting these MSCs would be endowed with regenerative capacity3.

Currently, the field has come to some sort of a consensus that these cells are not regenerative in nature except for a specific list of tissues (applications in bone, adipose, cartilage are the most common)4. Additionally, these cells have shown to be potent immune regulators and the majority and most promising clinical trials underway are focusing on diseases which would benefit from this characteristic such as Graft Versus Host Disease (GVHD), Crohn’s Disease and Rheumatoid Arthritis or to regenerate bone/cartilage tissues.

We hope in the future to see patients benefiting from this important development in the stem cell field.


  2. Caplan, A. I. Mesenchymal stem cells. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 9, 641–50 (1991).
  3. Pittenger, M. F. et al. Multilineage potential of adult human mesenchymal stem cells. Science (New York, N.Y.) 284, 143–7 (1999).
  4. Bianco, P., Riminucci, M., Gronthos, S. & Robey, P. G. Bone marrow stromal stem cells: nature, biology, and potential applications. Stem cells (Dayton, Ohio) 19, 180–92 (2001).

#science #research #stemcells #celltherapy #cells #HSCT #bonemarrow #LizarScience