The shape of things determines what they can do. Or, as a molecular biologist would phrase it, “structure determines function.”
In most ways, forks and spoons are similar. They’re made from the same materials, they show up alongside each other in place settings. But a spoon has a curved, solid bowl – you’d use it for soup or ice cream. A fork has prongs and is better suited for stabbing.
In matters of self defense, I’d reach for the fork.
On a much smaller scale, the three-dimensional shapes of a protein determines what it can do.
Each molecule of hemoglobin has a spoon-like pocket that’s just the right size for carrying oxygen, while still allowing the oxygen to wriggle free wherever your cells need it. A developing fetus has hemoglobin that’s shaped differently – when the fetal hemoglobin grabs oxygen, it squeezes more tightly, causing oxygen to pass from a mother to her fetus.
Each “voltage-gated ion channel” in your neurons has a shape that lets it sense incoming electrical signals and pass them forward. Voltage-gated ion channels are like sliding doors. They occasionally open to let in a rush of salt. Because salts are electrically charged, this creates an electric current. The electrical current will cause the next set of doors to open.
Every protein is shaped differently, which lets each do a different job. But they’re all made from the same materials – a long chain of amino acids.
Your DNA holds the instructions for every protein in your body.
Your DNA is like a big, fancy cookbook – it holds all the recipes, but you might not want to bring it into the kitchen. You wouldn’t want to spill something on it, or get it wet, or otherwise wreck it.
Instead of bringing your nice big cookbook into the kitchen, you might copy a single recipe onto an index card. That way, you can be as messy as you like – if you spill something, you can always write out a new index card later.
And your cells do the same thing. When it’s time to make proteins, your cells copy the recipes. The original cookbook is made from DNA; the index-card-like copies are made from RNA. Then the index cards are shipped out of the nucleus – the library at the center of your cells – into the cytoplasm – the bustling kitchen where proteins are made and do their work.
When a protein is first made, it’s a long strand of amino acids. Imagine a long rope with assorted junk tied on every few inches. Look, here’s a swath of velcro! Here’s a magnet. Here’s another magnet. Here’s a big plastic knob. Here’s another magnet. Here’s another piece of velcro. And so on.
If you shake this long rope, jostling it the way that a molecule tumbling through our cells gets jostled, the magnets will eventually stick together, and the velcro bits will stick to together, and the big plastic knob will jut out because there’s not enough room for it to fit inside the jumble.
That’s what happens during protein folding. Some amino acids are good at being near water, and those often end up on the outside of the final shape. Some amino acids repel water – like the oil layer of an unshaken oil & vinegar salad dressing – and those often end up on the inside of the final shape.
Other amino acids glue the protein together. The amino acid cysteine will stick to other cysteines. Some amino acids have negatively-charged sidechains, some have positively-charged sidechains, and these attract each other like magnets.
Sounds easy enough!
Except, wait. If you had a long rope with dozens of magnets, dozens of patches of velcro, and then you shook it around … well, the magnets would stick to other magnets, but would they stick to the right magnets?
You might imagine that there are many ways the protein could fold. But there’s only a single final shape that would allow the protein to function correctly in a cell.
So your cells use little helpers to ensure that proteins fold correctly. Some of the helpers are called “molecular chaperones,” and they guard various parts of the long strand so that it won’t glom together incorrectly. Some helpers are called “glycosylation enzymes,” and these glue little bits and bobs to the surface of a protein, some of which seem to act like mailing addresses to send the protein to the right place in a cell, some of which change the way the protein folds.
Our cells have a bunch of ways to ensure that each protein folds into the right 3D shape. And even with all this help, something things go awry. Alzheimer’s disease is associated with amyloid plaques that form in the brain – these are big trash heaps of misfolded proteins. The Alzheimer’s protein is just very tricky to fold correctly, especially if there’s a bunch of the misfolded protein strewn about.
Many human proteins can be made by bacteria. Humans and bacteria are relatives, after all – if you look back in our family trees, you’ll find that humans and bacteria shared a great-great-great-grandmother a mere three billion years ago.
The cookbooks in our cells are written in the same language. Bacteria can read all our recipes.
Which is great news for biochemists, because bacteria are really cheap to grow.
If you need a whole bunch of some human protein, you start by trying to make it in bacteria. First you copy down the recipe – which means using things called “restriction enzymes” to move a sequence of DNA into a plasmid, which is something like a bacterial index card – then you punch holes in some bacteria and let your instructions drift in for them to read.
The bacteria churn out copies of your human protein. Bacteria almost always make the right long rope of amino acids.
But human proteins sometimes fold into the wrong shapes inside bacteria. Bacteria don’t have all the same helper molecules that we do,.
If a protein doesn’t fold into the right shape, it won’t do the right things.
If you were working in a laboratory, and you found out that the protein you’d asked bacteria to make was getting folded wrong … well, you’d probably start to sigh a lot. Instead of making the correctly-folded human protein, your bacteria gave you useless goo.
But fear not!
Yeast can’t be grown as cheaply as bacteria, but they’re still reasonably inexpensive. And yeast are closer relatives – instead of three billion years ago, the most recent great-great-grandmother shared between humans and yeast lived about one billion years ago.
Yeast have a few of the same helper proteins that we do. Some human proteins that can’t be made in bacteria will fold correctly in yeast.
So, you take some yeast, genetically modify it to produce a human protein, then grow a whole bunch of it. This is called “fermentation.” It’s like you’re making beer, almost. Genetically modified beer.
Then you spin your beer inside a centrifuge. This collects all the solid stuff at the bottom of the flask. Then you’ll try to purify the protein that you want away from all the other gunk. Like the yeast itself, and all the proteins that yeast normally make.
If you’re lucky, the human protein you were after will have folded correctly!
If you’re unlucky, the protein will have folded wrong. Your yeast might produce a bunch of useless goo. And then you do more sighing.
There’s another option, but it’s expensive. You can make your human protein inside human cells.
Normally, human cells are hesitant to do too much growing and dividing and replicating. After all, the instructions in our DNA are supposed to produce a body that looks just so – two arms, two eyes, a smile. Once we have cells in the right places, cell division is just supposed to replace the parts of you that have worn out.
Dead skin cells steadily flake from our bodies. New cells constantly replace them.
But sometimes a cell gets too eager to grow. If its DNA loses certain instructions, like the “contact inhibition” that tells cells to stop growing when they get too crowded, a human cell might make many, many copies of itself.
Which is unhelpful. Potentially lethal. A cell that’s too eager to grow is cancer.
Although it’s really, really unhelpful to have cancer cells growing in your body, in a laboratory, cancer cells are prized. Cancer cells are so eager to grow that we might be able to raise them in petri dishes.
Maybe you’ve heard of HeLa cells – this is a cancer cell line that was taken from a Black woman’s body without her consent, and then this cell line was used to produce innumerable medical discoveries, including many that were patented and have brought in huge sums of money, and this woman’s family was not compensated at all, and they’ve suffered huge invasions of their privacy because a lot of their genetic information has been published, again without their consent …
HeLa cells are probably the easiest human cells to grow. And it’s possible to flood them with instructions to make a particular human protein. You can feel quite confident that your human protein will fold correctly.
But it’s way more expensive to grow HeLa cells than yeast. You have to grow them in a single layer in a petri dish. You have to feed them the blood of a baby calf. You have to be very careful while you work or else the cells will get contaminated with bacteria or yeast and die.
If you really must have a whole lot of a human protein, and you can’t make it in bacteria or yeast, then you can do it. But it’ll cost you.
Vaccination is perhaps the safest, most effective thing that physicians do.
Your immune system quells disease, but it has to learn which shapes inside your body represent danger. Antibodies and immunological memory arise in a process like evolution – random genetic recombination until our defenses can bind to the surface of an intruder. By letting our immune system train in a relatively safe encounter, we boost our odds of later survival.
The molecular workings of our immune systems are still being studied, but the basic principles of inoculation were independently discovered centuries ago by scientists in Africa, India, and China. These scientists’ descendants practiced inoculation against smallpox for hundreds of years before their techniques were adapted by Edward Jenner to create his smallpox vaccine.
If you put a virus into somebody’s body, that person might get sick. So what you want is to put something that looks a lot like the virus into somebody’s body.
One way to make something that looks like the virus, but isn’t, is to take the actual virus and whack it with a hammer. You break it a little. Not so much that it’s unrecognizable, but enough so that it can’t work. Can’t make somebody sick. This is often done with “heat inactivation.”
Heat inactivation can be dangerous, though. If you cook a virus too long, it might fall apart and your immune system learns nothing. If you don’t cook a virus long enough, it might make you sick.
In some of the early smallpox vaccine trials, the “heat inactivated” viruses still made a lot of people very, very sick.
Fewer people got very sick than if they’d been exposed to smallpox virus naturally, but it feels different when you’re injecting something right into somebody’s arm.
We hold vaccines to high standards. Even when we’re vaccinating people against deadly diseases, we expect our vaccines to be very, very safe.
It’s safer to vaccinate people with things that look like a virus but can’t possibly infect them.
This is why you might want to produce a whole bunch of some specific protein. Why you’d go through that whole rigamarole of testing protein folding in bacteria, yeast, and HeLa cells. Because you’re trying to make a bunch of protein that looks like a virus.
Each virus is a little protein shell. They’re basically delivery drones for nasty bits of genetic material.
If you can make pieces of this protein shell inside bacteria, or in yeast, and then inject those into people, then the people can’t possibly be infected. You’re not injecting people with a whole virus – the delivery drone with its awful recipes inside. Instead, you’re injecting people with just the propeller blades from the drone, or just its empty cargo hold.
These vaccine are missing the genetic material that allow viruses to make copies of themselves. Unlike with a heat inactivated virus, we can’t possibly contract the illness from these vaccines.
This is roughly the strategy used for the HPV vaccine that my father helped develop. Merck’s “Gardasil” uses viral proteins made by yeast, which is a fancy way of saying that Merck purifies part of the virus’s delivery drone away from big batches of genetically-modified beer.
We have a lot of practice making vaccines from purified protein.
Even so, it’s a long, difficult, expensive process. You have to identify which part of the virus is often recognized by our immune systems. You have to find a way to produce a lot of this correctly-folded protein. You have to purify this protein away from everything else made by your bacteria or yeast or HeLa cells.
The Covid-19 vaccines bypass all that.
In a way, these are vaccines for lazy people. Instead of finding a way to make a whole bunch of viral protein, then purify it, then put it into somebody’s arm … well, what if we just asked the patient’s arm to make the viral protein on its own?
Several of the Covid-19 vaccines are made with mRNA molecules.
These mRNA molecules are the index cards that we use for recipes in our cells’ kitchens, so the only trick is to deliver a bunch of mRNA with a recipe for part of the Covid-19 virus. Then our immune system can learn that anything with that particular shape is bad and ought to be destroyed.
After learning to recognize one part of the virus delivery drone, we’ll be able to stop the real thing.
We can’t vaccinate people by injecting just the mRNA, though, because our bodies have lots of ways to destroy RNA molecules. After all, you wouldn’t want to cook from the recipe from any old index card that you’d found in the street. Maybe somebody copied a recipe from The Anarchist Cookbook – you’d accidentally whip up a bomb instead of a delicious cake.
I used to share laboratory space with people who studied RNA, and they were intensely paranoid about cleaning. They’d always wear gloves, they’d wipe down every surface many times each day. Not to protect themselves, but to ensure that all the RNA-destroying enzymes that our bodies naturally produce wouldn’t ruin their experiments.
mRNA is finicky and unstable. And our bodies intentionally destroy stray recipes.
So to make a vaccine, you have to wrap the mRNA in a little envelope. That way, your cells might receive the recipe before it’s destroyed. In this case, the envelope is called a “lipid nanoparticle,” but you could also call a fat bubble. Not a bubble that’s rotund – a tiny sphere made of fat.
Fat bubbles are used throughout cells. When the neurons in your brain communicate, they burst open fat bubbles full of neurotransmitters and scatter the contents. When stuff found outside a cell needs to be destroyed, it’s bundled into fat bubbles and sent to a cellular trash factories called lysosomes.
For my Ph.D. thesis, I studied the postmarking system for fat bubbles. How fat bubbles get addressed in order to be sent to the right places.
Sure, I made my work sound fancier when I gave my thesis defense, but that’s really what I was doing.
Anyway, after we inject someone with an mRNA vaccine, the fat bubble with the mRNA gets bundled up and taken into some of their cells, and this tricks those cells into following the mRNA recipe and making a protein from the Covid-19 virus.
This mRNA recipe won’t teach the cells how to make a whole virus — that would be dangerous! That’s what happens during a Covid-19 infection – your cells get the virus’s whole damn cookbook and they make the entire delivery drone and more cookbooks to put inside and then these spread through your body and pull the same trick on more and more of your cells. A single unstopped delivery drone can trick your cells into building a whole fleet of them and infecting cells throughout your body.
Instead, the mRNA recipe we use for the vaccine has only a small portion of the Covid-19 genome, just enough for your cells to make part of the delivery drone and learn to recognize it as a threat.
And this recipe never visits the nucleus, which is the main library in your cells that holds your DNA, the master cookbook with recipes for every protein in your body. Your cells are tricked into following recipes scribbled onto the vaccine’s index cards, but your master cookbook remains unchanged. And, just like all the mRNA index cards that our bodies normally produce, the mRNA from the vaccine soon gets destroyed. All those stray index cards, chucked unceremoniously into the recycling bin.
The Johnson & Johnson vaccine also tricks our cells into making a piece of the Covid-19 virus.
This vaccine uses a different virus’s delivery drone to send the recipe for a piece of Covid-19 into your cells. The vaccine’s delivery drone isn’t a real virus – the recipe it holds doesn’t include the instructions on how to make copies of itself. But the vaccine’s delivery drone looks an awful lot like a virus, which means it’s easier to work with than the mRNA vaccines.
Those little engineered fat bubbles are finicky. And mRNA is finicky. But the Johnson & Johnson vaccine uses a delivery drone that was optimized through natural selection out in the real world. It evolved to be stable enough to make us sick.
Now we can steal its design in an effort to keep people well.
Lots of people received the Johnson & Johnson vaccine without incident, but we’ve temporarily stopped giving it to people. Blood clots are really scary.
You might want to read Alexandra Lahav’s excellent essay, “Medicine Is Made for Men.” Lahav describes the many ways in which a lack of diversity in science, technology, and engineering fields can cause harm.
Cars are designed to protect men: for many years, we used only crash test dummies that were shaped like men to determine whether cars were safe. In equivalent accidents, women are more likely to die, because, lo and behold, their bodies are often shaped differently.
Women are also more likely to be killed by medication. Safety testing often fails to account for women’s hormonal cycles, or complications from contraceptives, or differences in metabolism, or several other important features of women’s bodies.
White male bodies are considered to be human bodies, and any deviation is considered an abnormal case. Medication tested in white men can be approved for everyone; medication tested in Black patients was approved only for use in other Black patients.
Although more than half our population are women, their bodies are treated as bizarre.
For most people, the Johnson & Johnson vaccine is safe. But this is a sort of tragedy that occurs too often – causing harm to women because we’re inattentive to the unique features of their bodies.
I haven’t been vaccinated yet, but I registered as soon as I was able – my first dose will be on April 26th. Although I’ve almost certainly already had Covid-19 before, and am unlikely to get severely ill the next time I contract it, I’m getting the vaccine to protect my friends and neighbors.
So should you.