Tag Archives: science

10x Genomics: what happened to all the DNA stocks?

2020 was the year of COVID, but it was also the year of DNA. Thousands of DNA companies and researchers got in on the pandemic since there was a sudden surge in demand for COVID testing, contact tracing, and virus studying. Now, COVID is an RNA virus, but RNA and DNA work so similarly that most organizations that do one can do both. Even the Universities got into it, I know the Genomics Research Core Facility at the university I used to work for got money from city, state, and federal governments to process COVID tests, which was way more profitable for them than sequencing my plasmids once a month.

So 10x Genomics was a DNA sequencing company that, like so many others, skyrocketed in valuation during 2020. It hit its absolute peak in early 2021 and then fell precipitously through 2022. That describes a lot of companies but it especially seems to describe DNA companies. Still, I wanted to know if 10x Genomics was a buy, and considering my LinkedIn account got spammed all last year with recruiters and ads for the company, I figured they were at least worth a look. The result? A resounding “eh.”

One of 10x Genomics’ big claims to fame is their ability to perform reads of long segments of DNA as opposed to the shorter segments read by rival Illumina. Sequencing DNA gets less accurate the longer the DNA is, so Illumina and others use a technique of chopping the DNA into pieces, sequencing each piece, and putting them all back together. This usually works fine because there are enough overlapping pieces to make the puzzle fit, if you know read 3 different pieces with letters “AATT”, “TTGG” and “GGCC” then you can hazard a guess that the full sequence reads “AATTGGCC” and that the 3 pieces simply overlapped each other. This doesn’t work with long sequences of a single letter or repeating patters. If you simply have “AAAA” “AAAA” “AAAA” then you actually don’t know how long that string of As is. Those 3 reads could overlap on 2 letter and the result could be “AAAAAAAA” or they could overlap completely and the result is simply “AAAA.” About 8% of the human genome is these sorts of repeating patterns that Illumina and others are ill-equipped to read, which gives 10x an exploitable niche.

Now this is a genuinely interesting piece of equipment and their barcoding of DNA segments to read them in the correct order is a nice bit of chemistry, but was this a company that was ever worth 21 billion dollars? In my opinion *no*. The COVID era was a bubble in a number of ways, the easy-money policies of the post Financial Crisis era led to the super-duper-easy-money policies of the COVID era. Operation Warp Speed and other pandemic-focused funding sources meant that money was flowing into the biotech sector, and with most of the world still coming out of lockdown investors were desperate to park their money in companies that were still able to operate. It seemed like the moment for Biotech had come, and companies like 10x Genomics rode the wave to the very top. But from where I’m standing this was always an obvious bubble, and people were making claims about DNA companies that were woefully unfounded.

I’ve just written a lot about 10x Genomics, but all this could apply to most any DNA/RNA startup around. They all had neat ideas, got woefully overvalued during the pandemic, and have since crashed to earth taking shareholder value along with them. My question today then is why, why does it seem like Wall Street Investors saw something in DNA/RNA companies that I, a biology researcher, never did? Now part of that is that I’m just curmudgeony by nature, but part of that is that I think a lot of investors have this Sci-Fi idea of genetics in their head that isn’t really reflected in the field. I could just point to Cathie Wood and say “she doesn’t know Jack” but I want to dig a little deeper into some of the strange narratives that surround nucleic acids.

First, “DNA as a coding language.” I wonder if computer scientists just latch onto the word “code” or something, because the genetic code is no where near to being something that we can manipulate like computer code, and probably won’t be for decades. We’ve been inserting novel DNA into organisms since the 70s, but recently there’s been a spate of investors and analysts who believe that we’re on the cusp of truly programming cells, being able to manipulate them into doing everything we want as cleanly and as easily as a computer. This would definitely unlock a whole host of industries, it’s also not going to happen for a long while yet. DNA codes for proteins, and proteins are the functional units of most biological processes. Nothing you change in the DNA matters until it shows up in the proteins, and we are far, FAR from being able to understand how to manipulate proteins as easily as we do computers. You cannot simply say “let’s add a gene to make this wheat crop use less water,” you have to find a protein from another plant that causes it to use less water, insert that gene into wheat, do tests to make sure the wheat crop tolerates the new protein, alter the protein to account for unexpected cross reactions, and then finally test your finished wheat product out to make sure it works as designed. Any one of these steps could require an entire company to do, and each step could prove impossible and bankrupt the company working on it. We can’t just make de novo proteins to do our bidding because we don’t even know yet how to predict what a protein will look like when we code for it. Folding at home and other machine learning projects have helped us get partway there, but it will still take many Nobel Prizes before we can make de novo proteins as easily as we make de novo programs. So while there is a genomics revolution going on, it’s still an expensive and time consuming one, it’s not going to solve all our problems in a single go.

Second, “DNA as a storage medium.” I’ve said before that while DNA does store and transmit information, that information cannot be well integrated with our modern technology. The readout of DNA information is in RNA and proteins, while the readout of the circuits in your computer is photons on a screen or electrons in a modem. RNA and proteins do not easily produce or absorb electrons and photons, so having DNA communicate with our current technology is not currently doable. In addition, the time lag between reading DNA and making RNA/proteins is astronomical compared to the speed of information retrieval in semiconductors. I sometimes get an annoyed by the seconds-long delay it takes to load a webpage, but I’d be tearing my hair out if I had to wait on the minutes-long delay for DNA to be transcribed into RNA! At this time I really don’t see any reason to use DNA as a storage medium and I certainly don’t see a path to profit for any company trying to use it as such.

Third, curing genetic diseases. There is definitely a market for curing genetic diseases, let me just say that first, but many of the hyped-up corporate solutions are not feasible and rely more on sci-fi than actual science. I’ve discussed how even though CRISPR can change a cell’s DNA, bringing the CRISPR and cell together is much more challenging. The human body has a lot of defenses to protect itself from exogenous DNA and proteins, and getting around those defenses is a challenge. But in addition I don’t think investors realize that DNA is not the end-all be-all of genetic diseases, and so they tack things on to the Total Addressable Market (TAM) of DNA companies that shouldn’t really be there. Then they get flummoxed when the company has no path to addressing its TAM. Valuing companies based on what they can’t do is a bad investment strategy that I see over and over again with DNA companies. As to genetic disease themselves: there’s a truism in biology that “you are what your proteins are”. Although DNA codes for those proteins, once they’re coded they act all on their own, and some of their actions cannot readily be undone. When a body is growing and developing, its proteins can act up in ways that cause permanent alterations, and after they’ve done so changing the DNA won’t change things back. There are a number of genetic-linked diseases which are not amenable to CRISPR treatment because by the time the disease is discovered the damage has been done and changing the DNA won’t undo the damage.

Finally, “move fast and break things” doesn’t work with DNA the way it does with computers. I’ve worked on both coding projects and wet-lab projects. When something goes wrong in my computer code, fixing it is a long and arduous process but I have tools available that let me know what exactly the code is doing every step of the way. I can step through the code line by line and find out exactly what went wrong, and use that knowledge to fix things. Nothing is so straightforward when working with DNA, your ability to bugfix is only as good as your ability to read the code and reading DNA is a difficult and time-consuming process. Not only that, remember how I said above that we don’t know the exact relation between the DNA we put in and the DNA product we get out? If I’m trying to make a novel protein using novel DNA and it doesn’t get made, what went wrong? I can’t step through the code on this one because there’s no way to read out the activity of every RNA polymerase, every ribosome, or every post-transcriptional enzyme in the cell. I can make hypotheses and do experiments to try to guess at what is going on, but I can’t bugfix by stepping through the code, even using Green Fluorescent Protein as a print(“here”) crutch is difficult and time consuming. Even if I try to bugfix, the time lag between making a change and seeing the results can be weeks, months, or years depending on what system I’m working in, a far cry from how long it takes to compile code! A DNA-based R&D pipeline just doesn’t have the speed necessary to scale the way a coding house does, once you’ve got a program working the cost of sharing it is basically zero and the cost of starting a new project isn’t that great. That speed isn’t’ available to DNA companies yet.

This was a lot of words not just on 10x Genomics but on DNA-based companies in general. The pandemic-era highs may never be seen again for many of these companies, much like how some companies never again saw the highs of the Dotcom bubble. I think it’s important for investors to take a level-headed approach to DNA-based companies and not get caught up in the sci-fi hype. Anyone can sell you an idea, it takes a lot more work to make a product.

Quick post: naysayers aren’t always wrong

There was recently a nuclear fusion “breakthrough” which brought the naysayers out of the woodwork. The breakthrough claimed that scientists had used fusion to generate more energy than was put in. This claim, however, discounted the energy cost of the lasers used to achieve the fusion, which is like saying your company is profitable is you ignore all the salaries. Not only that, this breakthrough isn’t even on the way to creating a self-sustaining fusion reaction, it can not create a self-sustaining reaction due to the need to add and target new material in between each laser pulse. This “breakthrough” is seeming more and more like a nothingburger, and the naysayers have come out to say nay on it.

This has led to the usual backlash from the yaysayers: “they said at airplanes and steamships would never work! You’re ignorant if you don’t believe fusion won’t work!” It’s true that naysayers often laugh and disparage the geniuses of the age, they laughed at the Wright Brothers, they laughed at Edison, but remember they also laughed at Bozo the clown. Yaysayers don’t ever seem to acquiesce to the numerous promised technologies that never really worked, only focusing on those that did work and claiming a direct connection to the current one. So I thought I’d illuminate some prior failures.

Flying cars: everyone knows that the promise of flying cars never panned out despite much public mindshare and media hype. You may counter that “flying cars aren’t impossible, trying to make them is just expensive, difficult, and unnecessary” to which I say “perhaps so is fusion.” The possibility of making a toy-flying car which would never be road-legal is akin to using 300 megajoules to get 3 megajoules out of a fusion pellet, and claiming you have a breakthrough. Doable yes, but it doesn’t prove the endeavor to be doable at scale.

Antigravity elevators. Albert Einstein made several attempts at unifying the (then known) forces of the Universe together. When he started, physicists only knew about electromagnetism and gravity, but it was very enticing that these forces act so similarly in that they have infinite range and their power falls off with the square of the distance. Einstein and others theorized that there was some way to change electricity into gravity and vice versa, and charlatans/”inventors” jumped on the idea. One theory was an antigravity elevator which, by transporting passengers up and down through gravity waves instead of a moving cab, would be much more efficient and perhaps easier to maintain. Of course this idea never came to pass, not least because theories on the unification of gravity with electromagnetism were still missing half the puzzle: the strong and weak nuclear forces.

And here’s a great one: Supersonic flight transport aircraft. Now this might seem a weird one, Concorde showed it isn’t impossible, but as I’ve discussed before history has shown it to be clearly uneconomical when compared to its competitors. An idea doesn’t have to be impossible to get tossed aside, merely uneconomical.

I feel like people don’t realize how many seemingly great ideas have come and failed because they just aren’t economical even if they aren’t impossible. Fusion could well be one of those ideas, sure it works in physics but in economics who’s to say fission and renewables aren’t just objectively better? We’re still decades off even a working test reactor, and the one being planned is already about 4x over budget. Private companies have claimed they’ll come in and disrupt the industry but we had the same claims about a lot of failed projects over the years, who’s to say fusion will be any different? I know that fusion power as a scientific concept is perfectly sound, but as an engineering challenge or a profitable industry I remain skeptical.

Invest in what you know? How much do I need to know?

I’m a biochemical scientist. I’ve published papers. I’ve got degrees. As an investor, I’ve often been given the advice (whether from friends or randos on the internet) that to “invest in what you know” is the safest kind of investment. For me personally though, I’ve avoided investing in any particular biotech or med-tech companies outside of passive ETFs, because I feel like while I know a lot about biochemistry in general I don’t know enough in specific to have any kind of advantage in those areas. I know about Alzheimer’s disease, but I don’t know much about pharmacology so how would I discriminate between two Alzheimer’s drug companies I wanted to invest in? I know about CRISPR/Cas, but I don’t know enough about its delivery system in humans to feel confident that I could pick the winners in today’s more crowded CRISPR field. There are a lot of areas of biology that I feel I have a little knowledge, but not enough to give me an edge.

Maybe there’s a Dunning-Kruger effect here though, because while I can’t explain what cloud computing is besides “it’s like renting another person’s computer,” I have thrown a bunch of money into Microsoft and been happily watching it grow. I like my Microsoft products and my office suite, so I feel good enough about them that I feel they’re doing alright. Yet I clearly know a hell of a lot less about Microsoft than I do any of the biotech companies of the world, so why do I feel so confident investing here?

I don’t know, it’s hard to psycho-analyze myself, but am I making all the wrong moves? Should I focus on investing in biotech companies, confident that my background would give me an edge in picking the winners and avoiding the losers? For now, ETFs for me I guess, but I’ll keep blogging about them since they’re fun.

The nuclear fusion breakthrough that wasn’t

There was recently a nuclear fusion “breakthrough” which I just had to check out. I was disappointed to learn that this wasn’t a breakthrough at all, but a clever bit of marketing dressing up a modest scientific experiment. To explain what happened, a laboratory used around 300 megajoules of energy to create a 2 megajoule laser pulse. That pulse then hit a pellet of material, releasing 3 megajoules of energy as the pellet underwent nuclear fusion. The holy grail of fusion is a self-sustaining reaction, one necessity of such a reaction is that more energy must be released than is put in, and this experiment was hails as doing just that since the 3 megajoules of released energy is more than the 2 megajoule laser pulse. Yet that isn’t actually true because 300 megajoules went into creating that laser pulse, this is like saying a company is profitable if you ignore all salary costs. At the end of the day we want to develop a fusion reaction such that energy out > energy in, and this reaction simply did not do that.

I know why they tried to spin it this way, it’s a longstanding trick of pulsed-laser experiments to report only the amount of energy delivered by the laser, ignoring the amount of energy it takes to create that laser pulse. It makes your reactions seem a lot more efficient and feasible than they really are. But this kind of lying does the entire industry a disservice because it’s just more evidence on the pile of fusion-boosters overpromising and underdelivering. Reading this news you’d mistakenly believe we are now on the precipice of economical and available fusion power when in actuality we’re about as far as we’ve always been.

Beam Therapeutics: what’s so special about prime editing?

Beam Therapeutics is another biotech company often mentioned in the same vein as Ginkgo Bioworks, Amyris, and Twist Bioscience, and since I’ve blogged about all three of those I might as well blog about Beam. Unlike Ginkgo and Twist, Beam isn’t a shovel salesman in a gold rush, they’re actually trying to create drugs and sell them, in this case they’re trying to break into or perhaps even create the cutting edge industry of medical genetics, changing people’s genes for the better. I’ll briefly discuss the science of their technology, but I feel like the science surrounding their technology deserves the most focus.

Beam has a novel form of CRISPR/Cas gene editing called prime editing. In both normal CRISPR/Cas and prime editing, genetic information is inserted into a living organism by way of novel DNA, guide-nucleotides and a DNA cutting enzyme. The guide-nucleotides direct the information to the specific part of the genome where it is needed, the DNA cutting enzyme excises a specific segment of host DNA, and hopefully DNA repair mechanisms allow the novel DNA to be inserted in its place. These techniques always rely in part of the host’s own DNA repair mechanisms, you have to cut DNA to insert novel DNA and that cut must then be stitched back up. Most CRISPR/Cas systems create double-stranded breaks while prime editing creates just single stranded breaks, and this greatly eases the burden of the host DNA repair mechanisms allowing inserts to go in smoothly and with far less likelihood of catastrophic effects. Double stranded breaks can introduce mutations, cancers, or cause a cell to commit cell-suicide to save the rest of the body from its own mutations and cancers. Because Beam is using prime editing, their DNA editing should have less off-target effects and far less chances to go wrong.

So the upside for Beam is that they’re doing gene editing in what could be the safest, most effective way possible. The downside is that gene editing itself is still just half the battle.

When I look at a lot of gene editing companies, I quickly find all kinds of data on the safety of their edits, the amount of DNA they can insert or delete, and impressive diagrams about how their editing molecules work. I rarely see much info about delivery systems, and that’s because delivering an edit is still somewhat of an Achilles’s heel of this technology. In a lab setting you can grow any cell you want in any conditions you want, so delivering the editing machinery (the DNA, the guide-nucleotides, the enzymes) is child’s play. But actual humans are not so easy, our cells are not readily accessible and our body has a number of defense mechanisms that have evolved to keep things out and that includes gene editors. To give you an idea of what these defenses are like, biology has its own gene editors in the form of retroviruses which insert their DNA into organisms like us in order to force our body to produce more viral progeny, a process which often kills the host. Retroviruses package their edit machinery in a protein capsid which sometimes sits inside a lipid (aka fatty) envelope, and so the human body has a lot of tools to recognize foreign capsids and envelopes and destroy them on sight. These same processes can be used to recognize and destroy a lot of the delivery systems that could otherwise be harnessed for gene editing.

Some companies side-step delivery entirely, if it’s hard to bring gene editing to cells why not just bring the cells to gene editing. This was the approach Vertex Pharmaceuticals used in its sickle cell anemia drug, blood stems cells were extracted from patients and edited in a test tube, before being reinserted into the patients in order to grow, divide, and start producing non-sickled red blood cells. This approach works great if you’re working on blood-based illnesses, since blood cells and blood stem cells are by far the easiest to extract and reinsert into the human body. But for other illnesses you need a delivery method which, like a virus, is able to enter the organism and change its cells’ DNA from within.

So if Beam Therapeutics wants to deliver a genetic payload using their prime editing technology, they’re going to need a delivery system which obeys the following rules

  • It must be able to evade the immune system and any other systems which would degrade it before it finds its target cells
  • It must be able to be targeted towards certain cells so that it doesn’t have off target effects
  • It must be able to enter targeted cells and deliver its genetic package

So let’s look at the options.

Viruses have already been mentioned, and they can be engineered in such a way as to deliver a genetic package without causing any disease. However as mentioned they are quickly recognized and dispatched by the immune system whenever their are found, their protein shells being easy targets for our bodies’ adaptive immune system. Normal viruses get around this by reproducing enough to outcompete the immune system that is targeting them, but we don’t want to infect patients we just want to cure them, so using viruses that reproduce is off the table for gene editing.

A variety of purely lipid-based structures exist which can ferry a genetic package through the body. Our cell membranes are made of phospholipids, and phospholipids will naturally form compartments whenever they are immersed in water. Phospholipids also have the propensity to fuse with each other, allowing their internal compartments to be shared and anything inside them to move from one to the other. Packaging a gene editor inside phospholipids would be less likely to trigger the immune system, and they can be created in such a way that they target a particular cell type to deliver their genetic package. However random phospholipids can be easily degraded by the body, limiting how long they can circulate to find their target cell. Furthermore their propensity to fuse is both a blessing and a curse, allowing them to easily deliver their genetic package to targets but also making them just as likely to deliver it to any random cell they bump into instead. This means a lot of off-target delivery and the possibility for plenty of off-target effects

At the other end of the scale are nanoparticles made of metals or other compounds. Many methods exist to attach drugs to the outside of a nanoparticle and target that nanoparticle to a cell, however this in turn leaves the drug free to be interacted with and targeted by the immune system. For many drugs this is fine, but prime editing uses foreign proteins, DNA and free nucleotides and the body is downright paranoid about finding those things hanging around since that usually means the body has either a cancer or an infection. To that end, the body destroys them on site and triggers an immune response, which would severely curtain any use of nanoparticles to deliver a genetic package. Nanoparticles can also be designed hollow to allow for the prime editing machinery to fit snugly inside them, but this can lead to the machinery just falling out of the nanoparticle in transit and being destroyed anyway. You might say “well not a hollow sphere that fully surrounds the machinery so it can’t fall out?” But it does need to get out eventually if it wants to edit the cell, and if it’s encased in a solid sphere of metal it can’t do that. Enzymes to breach the metal would be cool but are impractical in this case.

Between these two extremes we have a number of structures made of lipids, proteins, polymers or metals, and they all struggle with one of these points. They can’t encase the machinery, or they can’t easily deliver the machinery, or they trigger an immune response, or they degrade easily, or they often cause off-target delivery. Delivery to the target is Step 0 of both prime editing and gene editing in general, and for the most part this step is still unsolved. I’ve visited several seminars where viral packages for delivering CRISPR/Cas systems were discussed, and while these seem some of the most promising vectors for gene editing they still have the problem of triggering the body’s immune system and being destroyed by it. The seminars I’ve watched all discussed mitigating that problem, but none could sidestep it entirely.

I do believe that Beam therapeutics has technology that works, their prime editing is clearly a thing of beauty. Beam is currently working on treatments for sickle cell anemia, as is Vertex Pharmaceutical, and as are most gene editing companies because it’s a blood-based disease that is amenable to bringing the cells to the gene editing machinery instead of having to go vice versa. But for anything where you can’t bring the cells to the editing, Beam isn’t quite master of it’s own fate because for prime editing to reach the cells of the body it will need to be delivered in some way and currently that’s an unsolved problem. Even a system that works to deliver some packages won’t necessarily work for all of them as size and immunity considerations change with the specific nature of the genetic package you’re delivering. I would also be worried about Beam’s cash burn, they are essentially pre-revenue and will need to do a lot of research before any of their drugs get to market or can be sold to a bigger player. I think they can survive for a long while by selling stock since their price has held up a lot better than other biotechs I’ve blogged about, but that’s good for them and not for a shareholder. As long as interest rates keep going up, I’ll treat pre-revenue companies with a wary eye.

Why do we still not know what causes Alzheimer’s disease?

Between 1901 and 1906, Alois Alzheimer began collecting data on the disease that would eventually bear his name. A patient with memory deficiency was autopsied after her death and her brain was found to contain amyloid plaques and neurofibrillary tangles. Around a half century prior in 1861, Guillaume-Benjamin-Amand Duchenne had described a disease that would bear his name, a form of muscular dystrophy, and like Alzheimer he had patient samples for study. In the next century and more both diseases would be studied and reported on, Duschenne Muscular Dystrophy was eventually linked to a single protein called dystrophin, and a number of FDA-approved treatments exist which target dystrophin and improve patient outcomes. Alzheimer’s disease was also linked to a protein, the amyloid plaques found by Alois contained a protein called amyloid beta. But while both diseases seem to have known causes, treatments for Alzheimer’s disease remain ineffective. What’s more, there is a growing body of evidence that the amyloid beta hypothesis for Alzheimer’s disease is on shaky ground. How is it that more than a century of study has not allowed us to even understand Alzheimer’s disease?

First, it must be said that the amyloid beta (Aβ) hypothesis for Alzheimer’s Disease (AD) didn’t come out of nowhere. Not only were the amyloid plaques found in Alzheimer’s patients coming from Aβ, but genetic evidence showed that the mutations associated with AD all seemed to affect the Aβ pathway. If the diagnostic criteria for AD included Aβ, and genetic evidence supported a role for Aβ, it seemed Aβ must surely be the cause of the disease. And further biochemical evidence supported a role for Aβ, for example when Aβ was shown to cause neuronal cell death in cultured nerve cells. The Aβ hypothesis even connects well with other diseases, Aβ acts as an aggregating prion and aggregating prions are known to cause other neurodegenerative diseases such as Creutzfeldt-Jakob Disease and Kuru. Note that some biochemists say a protein is only a prion if it comes from the prion gene of the human body, but like champagne this definition is expanding. So the Aβ hypothesis isn’t a hypothesis without support, it has strong biochemical evidence at the genomic and proteomic level, and fits in well with other brain diseases. It can certainly be said that Aβ proponents have ignored or downplayed evidence against the Aβ hypothesis, but that behavior is common in all disciplines. Science advances one funeral at a time.

Second, it should be recognized that AD is a difficult disease to study involving a difficult organ to study. AD affects memory and behavior by affecting the brain, those are processes and an organ that are still very opaque to us in general let alone in the context of AD. So AD is a disease we don’t understand affecting processes we don’t understand in an organ we don’t understand. Maybe we should feel grateful we even have drug candidates to begin with?

To bring this back to my own work, let me give you an example of the very small problem I am working on and the difficulties I am facing in getting data. We have a theory that there are different subtypes of AD. There is the rapid-onset (r-AD) subtype and the slow-onset or traditional (t-AD) subtype. We believe that this difference may be structural in nature, that the proteins causing r-AD and t-AD are the same but that they have different shapes. To this end, I am studying the structural variations of sarkosyl-insoluble proteins from AD patients.

OK what does that mean? I start by requesting patient samples from deceased AD patients matching either the r-AD or t-AD subtype. This is difficult because not everyone really agrees on the diagnostic criteria of these two subtypes (already we have problems!). Then once I have a patient sample, I perform a sarkosyl extraction. Sarkosyl is just a detergent like the one you wash your clothes with. A detergent can dissolve some things (like the dirt on your clothes) while not dissolving other things (like the pigments coloring your clothes). Previous studies have shown that the proteins causing AD are sarkosyl insoluble, so just like how laundry detergent will wash away dirt while leaving behind pigments, I can use sarkosyl to wash away non-AD proteins and keep the AD-causing proteins. These sarkosyl insoluble proteins include Aβ, but also include things like Tau and alpha-synuclein which some people hypothesize are the true cause of AD. The sarkosyl extraction is difficult, and I seem to fail at it as often as I succeed, am I just bad at my job or is this all really really hard? I hope it’s the latter but you never know. Then, once I’ve extracted the material I need from the patient’s brain, I use a variety of techniques to try to test our theory about AD. I can see if the extracts from r-AD and t-AD brains have different affects on neuronal organoids (artificial culture of cells that resembles an organ, in this case a brain), I can image the extracts with electron microscopy, I can take structural measurements with NMR, and so far all the data is frustratingly vague. I haven’t been at this job super long, but I can tell you I am not finding the One True Cause of Alzheimer’s disease any time soon.

And I think my struggles are fairly representative of the AD-researching community at large, or at least the ones I’ve talked to. It’s a disease that can only be studied biochemically post-mortem, the samples you get are both very limited and highly variable, it’s hard to relate the biochemistry back to the behavior and memory because we don’t have very good theories about that stuff to begin with, and we’re trying to use all the latest and greatest techniques to study this but we’re still struggling to get strong evidence to support our theories. After a century and more of study, we still don’t seem to be anywhere close to curing Alzheimer’s, we can’t really treat it, and we barely understand it. It can be frustrating and difficult work

Science Update: why is Jose Romero spreading vaccine disinformation?

In November, the CDC declared it would expand wastewater testing for the detection of polio in America. The polio virus has unfortunately returned to American shores, decades after we had thought it eradicated. Jose Romero is CDC NCIRD (National Center for Immunization and Respiratory Diseases) director, and had this to say:

“When will we know that we’re out of the woods? When we get our vaccine rates at the national level — 93 or 94 percent — to have herd immunity in the community,” Romero said, referring to when enough individuals have been vaccinated so their collective immunity prevents the virus from circulating in that population

Via Washington Post

A fine sentiment, and a call for greater vaccination. Which would be all well and good if Romero’s statement on vaccines causing herd immunity wasn’t total disinformation. Before I get to why this statement is false, I first want to discuss why I’m writing this and why this is important. American public health has taken a blow over the past several years and in many ways this can be traced back to people’s growing distrust of public health officials. The causes for this distrust are varied, but because of the mistrust it is imperative that public health officials deliver accurate and relevant information to the public to help regain the public’s trust. I find it hard to believe that Jose Romero, who is an MD and the CDC NCIRD director, does not know or realize that his statement is false. I find it more likely that he is telling a public health white lie of the type that has become all too common, saying something false in order to encourage behavior he’d like to see. In this case, he wants to encourage more vaccine uptake, so instead of saying the truth (that the American polio vaccine only protects the recipient from paralytic polio and does not promote herd immunity or reduce community spread), he is saying something that he thinks will get more unvaccinated people to want to get the vaccine. The problem is that what he’s saying is wrong, actual scientists can tell us he’s wrong, and agenda-driven actors can then use his wrongness to discredit whatever else he is trying to say.

It you want two MDs to explain why Jose is wrong, This Week in Virology has you covered, but I will explain as best I can.

The polio virus is known to cause paralysis, but this is a secondary effect, the virus primarily infects the intestines. About 90% of people infected with polio will develop either no symptoms, or mild symptoms (fatigue, fever, diarrhea etc) but not paralysis. In 1% of polio infection the virus then spreads throughout the central nervous system, causing damage to nerve cells which leads to muscle paralysis. There are two main classes of vaccine that can protect against polio, the oral polio vaccine (OPM) and the inactivated poliovirus vaccine (IPV). It’s important to note that America only uses the IPV. The OPM contains a weakened form of the virus which is capable of replicating, and because it can replicate this weakened virus can then be passed on to others, infecting them as well and potentially causing paralysis in them. However this vaccine allows the entire immune system to come in contact with the virus and build defenses against it. The IPV does not contain a virus, only pieces of the virus are injected into the patient. Because of this, the virus cannot replicate and thus cannot be spread to others, but it also does not immunize as strongly as the OPM. So what if someone who received the IPV comes into contact with poliovirus? They are not so strongly immunized, so the virus can still replicate inside them and be excreted in the stool. But they are immunized enough to be protected against the major polio symptoms especially paralysis.

So to recap: the OPM is effective at preventing people from acquiring and spreading polio, but because it contains an actual virus, there are major downsides that must be considered. The IPV is not effective at preventing people from acquiring and spreading polio, but it prevents all the worst symptoms and has less downsides to its use. America only uses the IPV, so increasing our vaccination uptake will not prevent the acquiring or spreading of poliovirus and will not lead to herd immunity. The vaccine used in America only prevents people from getting paralyzed if they get infected with polio.

I think Jose Romero (or his staff) must know this, but I think they (like too many public health officials) are trying to influence behavior by shading the truth. This is a pattern of behavior that Josh Barro has also chronicled, dishonest framing has been used to obscure the truth for ostensibly noble ends. But lying doesn’t help, when people realize you’ve lied they become far less likely to trust you later. And for our nation’s public health community to continue this further decline in trust could prove disastrous.

Short post today: green hydrogen isn’t always

“Green” hydrogen power has become something of a minor meme industry. Hydrogen power (or “fuel cells”) is used to burn elemental hydrogen with elemental oxygen producing only water as a waste product. This industry has long been the fantasy of those who want to reduce our reliance on fossil fuels and prevent the accumulation of carbon in our atmosphere, the problem is that the most economical way of producing elemental hydrogen does neither. Hydrogen is usually produced from natural gas, but “green hydrogen,” could theoretically be created by splitting water into hydrogen and oxygen. Recently I read a story of a company seeking out tax breaks to produce green hydrogen from water, but the company isn’t interested in installing solar or wind power and using that for their purposes, they want to simply buy power from the grid and use it directly. The problem is that most of America’s grid isn’t actually powered by green power but by fossil fuels. This so called “green hydrogen” would simply use the electricity from fossil fuels to produce hydrogen, with no analysis done as to whether this would produce more or less greenhouse gases than producing hydrogen from natural gas instead. In this case then, green hydrogen may not be so green.

Synthetic biology: why it still might be a miracle industry

I’ve spent most of the last 2 weeks ragging on a few of the hottest SynBio startups. I’ve pointed out that these synbio startups have a very difficult path to profitability, and some might not even have a working business model. But from the scientific side, there’s still a revolution out there for synthetic biology, and I want to explain it.

To start with, the insulin and drug products revolution is a definite win for synthetic biology. The ability to take any gene, clone it into a bacteria or yeast cell, and then express it and collect the product is what has made many drugs so much cheaper than they were decades ago when we had to extract the drugs from animal carcasses or massive amounts of plant matter. It has also allowed revolutions in the types of drugs we can study and offer to patients, just about any protein you can think of could be turned into a drug that is usable for patients. Antibodies are a special type of protein which can also be produced through synthetic biology, and many antibody products have hit the drug market to treat all kinds of diseases. Aducanumab is one such antibody, a much hyped drug for treating (or rather slowing the progress of) Alzheimer’s disease. Quick note: you can tell if a drug contains an antibody by it’s name: aducanumab’s name ends in “mab” which stands for “monoclonal antibody.” Gemtuzumab (AML drug), Tezepelumab (severe asthma), pretty much any drug who’s name ends in “mab” is an antibody drug, and almost always they are produced through synthetic biology.

Biology can also catalyze certain reactions that chemistry can’t easily do. The classic example of this is creating molecules with specific stereochemistry. This will be a bit technical, but consider your left and right hand: they both have 4 fingers and a thumb but they are mirror images of each other, you can’t put your left hand in a right-handed glove and vice versa. In chemistry we would call left and right hands “stereoisomers” of each other, and just as with hands and gloves you can’t put left-handed molecules into places that require right-handed molecules. But chemically stereoisomers are identical, they have almost the exact same chemical properties and so a reaction which produces one stereoisomer will usually produce all possible stereoisomers in equal amounts. Image you wanted to produce only right hands, your starting material is the assembled 4-finger-plus-palm, now you just have to add the thumb in the correct place. Ignoring that the 4 fingers are of unequal length, if you put the thumb on one side of the fingers you get a right hand, while if you put the thumb on the other side of the fingers you get a left hand. A chemical reaction will make an equal number of right hands and left hands because it will add the thumb randomly to both sides. A reaction catalyzed by an enzyme however will only put the thumb on one side, the side you picked, and thus using an enzyme you can ensure you only make right hands and not left hands. This is another place where synthetic biology can be critical, there are many stereoisomers where one isomer is a useful drug and the other isomer may be a harmful chemical, we need to have some process to create only one of them and for that engineering enzymes with synthetic biology can yield good results.

Finally biology can greatly catalyze reactions in a way that greatly reduces the amount of energy we have to put into the system. Make no mistake, catalysis doesn’t yield free energy, but it does lower the energy barrier for a reaction. To turn carbon dioxide into some non-harmful form of carbon, we would chemically have to pump in a lot of energy to break the carbon-oxygen bonds which hold it together. That energy would require a high temperature and high pressure, which would then require containment, meaning scrubbing carbon from the atmosphere chemically is a very difficult process. However plants remove carbon dioxide every day, and do so at the modest temperatures and pressure that we find anywhere on Earth. They can do this because they use enzymes to catalyze the reaction, which lowers to energy barrier for the reaction to proceed forward. IF carbon capture technology ever becomes economically viable, mark my words it will have to be done using enzymes.

So synthetic biology allows us to tap into biological processes to perform jobs that are difficult to do chemically. The tools we have to do so, the genetic code of living organisms, also provide us with a vast array of starting tools to choose from to make things easier since we aren’t starting from scratch. And finally the fact that living organisms will grow and develop from things as simple as sugar instead of requiring oil or rare earth metals means that synthetic biology can be done just about anywhere and isn’t as limited by commodity costs like most other industries. In short, I DO believe synthetic biology may be the future, but I’m just not sure the current crop of biotech upstarts have what it takes

Amyris: might they be profitable?

Amyris ($AMRS) is another small-cap biotech that alongside Ginkgo ($DNA) and Twist ($TWST) has lost over 50% of its value year-to-date. With a stock price of ~2$ and a market cap of less than a billion, I think they technically qualify as a “penny stock” so all the usual caveats about volatility and such apply here. With that said, Amyris might be the better positioned company out of the 3. While Ginkgo wants to be the Apple App Store and take a cut out of everyone else’s money, Amyris is content to make money themselves by making and selling biosynthetic products. In the first 3 quarters of 2022, they made 194 million dollars a year in revenue, and spent 610 million dollars (GAAP) in order to do so. They had 483 million dollars of cash in December of 2021, but only 18 million in cash was left at the end of 2022 Q3. It all seems rather unsustainable and what’s worst is that only 81 million dollars of their expenses come from R&D ie most of the expenses are just running the business. Cost of products was 170 million, Sales+Admin was 358 million, and revenue remember was 194 million.. But if you fired all the salesmen, administrators, and R&D people they might theoretically be making a profit, whereas Ginkgo expects to make a profit from licenses that may never materialize and Twist is being accused of selling products for less than their cost.

That does not mean Amyris is a good investment, even in this theoretical world where they made 26 million dollars in earnings they would have a P/E north of 200, and not even Amazon trades that highly these days. Still revenue has been growing close to 100% year on year, and there is perhaps a profitable company somewhere inside Amyris that could be worth your money.

Amyris is interesting to me because they appear to be the most “pure play” of the synthetic biology micro-caps that I see talked about. Ginkgo and Twist both operate on the “shovel salesman” business model, the old chestnut that in a gold rush you’d rather be a shovel salesman than a miner. Ginkgo wants to license the GMOs that would produce synthetic biology products, Twist wants to sell the DNA that goes into those GMOs, but Amyris is actually doing the work of making biosynthetic products and selling them on. And what are they producing? Well beauty products, mostly.

Most of Amyris’ products are a good window into the synthetic biology world. There was some chemical discovered ages ago that was useful to humans, but it only came from a rare plant or animal, so we humans would harvest these plants and animals by the billions to extract the chemical and put it in whatever product we needed. Then synthetic biology comes along and finds a way to produce the chemical in a microorganism instead. The benefits in cost for this should be massive, but they don’t seem to be showing up in Amyris’ balance sheet. Instead the biggest benefits appear to be in Amyris’ branding and product ethics. There’s been a years long push to make products be “less cruel” depending on one’s definition. For some consumers this means products should not be made using animals, for others they should not be extracted from conflict zones, still others demand the products be made with only unionized or at least well-paid labor. Everyone has their own definition of ethical consumption, and their own boundaries that they will not cross. Importantly our boundaries usually depend on how necessary we find that product for our daily lives, some folks will only drink Fair Trade coffee but some will take any cup of joe served by an underpaid Starbucks employee because they need their caffeine and need it now. Beauty products sit right at the top of Mazlow’s hierarchy of needs and so the consumers of these products can demand as much ethics as they want because the consumer doesn’t really “need’ them and the producer knows it. There’s also the fact that beauty products are already sold to us as an avenue of self-expression, and for some folks moral/ethical self-expression is the most important type of all. To this end, beauty products have recently tried to show themselves as world leaders in ethical consumption, advertising that they have no animal cruelty, don’t contain products from combat zones, aren’t produced by underpaid laborers, and all sorts of ethical guarantees. This is a place where Amyris and other synthetic biology companies should have the greatest benefit because there are very few ethical concerns to making a product in a Silicon Valley lab using micro-organisms. To that end, it’s not surprising to me that beauty products are so far Amyris’ strong suit.

But beauty isn’t the end all be all, there are stories floating around on social media that Amyris only pivoted to beauty in a desperate attempt to get cashflow and save the company. It still might not work because they’re burning cash and have little of it left on hand. But if it works, the higher ups (it is claimed) still want to make all the other synthetic biology products you can think of, plastic substitutes, green hydrogen, novel drugs those kinds of things. It’s a lofty goal and if Amyris can do it and make a profit then I’d invest. But right now they’re still burning cash and their fate is likely tied to how far and fast the Fed tightens the money supply. Only time will tell.