Nick and Nora, Sid and Nancy, Notch and Delta

Hey, science lovers! I'd like to point out that Dr. K. George Chandy himself commented on my last post. He provided the link for the paper ("K+ channels as targets for specific immunomodulation") if you're interested in his work.

But that's old news! Today's news is this: signaling pathways are hilarious. One of my favorites is Notch/Delta.

Notch and Delta are proteins in Drosophila. All the cool stuff happens in fruit flies. Of course, the cool stuff happens in humans too; we just call the players by less cool names.

Notch and Delta are a receptor and a ligand, respectively. Delta is the baseball that fits into Notch's mitt. But why are we playing baseball in the first place?

See, when two fruit flies really love each other...well, you know the rest. Their little bundle of joy is going to need a nervous system. During the early stages of development, though, the cells are all kind of the same because they don't know what to do. They don't know what to become. They have not been given their life's ambition, their purpose.

Let's take a look at one such cell. Call her Veronica. Veronica is destined to become a mechanosensory bristle on the body of Lil' Fly. You know, the little touch-sensitive hairs. Veronica really, really wants to be a bristle, but first, she has to out herself as the sensory mother cell (SMC). Now she knows that if she becomes an SMC, the cells around her (let's call them Duncan, Troy, Leo, and Logan) can't be SMCs as well. You don't want a fruit fly that's one big hairy bundle of bristles.

Duncan and the boys kind of want to end up bristles too, though. Being a bristle is a pretty sweet gig. You get to react to the environment and let the fly know what's going on. It's an important job!

Now, all of our cells here are expressing Delta, just throwing it out like a pop fly (no pun intended). And they've also got Notch on the surface, all, "I've got it! I've got it!"

But here's the deal: if Notch catches Delta, it becomes activated. And it tells the cell not to become an SMC. It gets better, though, and this is the hilarious part: it throws out less Delta. See, the only way it has a fighting chance of becoming an SMC is if it keeps the cells around it from throwing out so much Delta. And the only way to do that would be to activate Notch in them so that they throw out less Delta. And the only to do that would be to throw out more Delta. EXCEPT IT CAN'T AHAHAHAHAHA.

Troy can try all he wants to toss out enough Delta to become king of the hill. They can all try; it's fun and in the spirit of competition. But the very instant Veronica gets the advantage (and she will, because it's her destiny), the game is over. Because she throws out more Delta, the boys throw out less Delta, which means fewer of her Notch receptors are activated, allowing her to throw out even more Delta. All their Notch receptors are hella activated, and hers just sit there inactivated like whoa. This is called lateral inhibition: she's keeping all the adjacent cells from following the same path she is. And it's nothing personal, guys! It would be dangerous and catastrophic for the full organism! You've got to take one for the team. Being an epithelial cell is still kinda cool.

I mean, not as cool as being a bristle, but still.

So that's Notch/Delta in a nutshell. It's a harrowing tale of power struggles, establishing dominance, and kicking cells when they're down.

Harry Potter and the Order of the T Cells

Today, I bring you a story of why science is awesome. It is the story of Dr. K. George Chandy at the University of California at Irvine. I'll try to keep the technical terms to a minimum.

Our story begins about twenty years ago, when Dr. Chandy finds that T cells express Kv1.3, a potassium channel.

T cells are part of your immune system. They recognize things in your body that don't belong, and then they kill the crap out of them. There are three types of T cells important to this story. First, we have the naive T cells. As their name implies, they're pretty ignorant. They don't know anything. Once they encounter something potentially dangerous (an antigen), however, they become memory T cells. They remember what these foreign invaders look like so that, if they return, they're ready to kick them out again. Finally, there are effector memory T cells. These cells not only remember what invaders look like, but they will attack them themselves.

Now, see, in a normal, healthy person, there's no reason to have a bunch of effector memory T cells. You would only have a large supply if you were fighting a chronic infection, something that required a constant battle, something that demanded your immune system get involved.

Like, Dr. Chandy thinks, an autoimmune disorder. Multiple sclerosis, Type I diabetes, rheumatoid arthritis, etc. All these diseases have the immune system turning on itself, fighting foreign invaders that are actually the body's own tissue.

So he takes a look at the model. For a T cell to be activated, it must first recognize the antigen. When it docks with this cell, it triggers a release of intracellular calcium. But this isn't enough calcium for it to get jiggy with it, so it turns to Calcium Release Activated Calcium (CRAC), a channel that will allow more calcium into the cell.

There's a small problem, though. Calcium is positively charged, and since you've got all this calcium coming in, you need to get rid of some other positively charged ion to balance things out. This is where potassium channels come in. A T cell has two: Kv1.3 and KCa-something-or-other. In fact, we'll just call them Kv1.3 and The Other One. The key point here is that in order for this T cell to function, it needs at least one of these potassium channels.

Now, Dr. Chandy has this crazy theory, see. He thinks you can preferentially target the effector memory T cells (the ones actually responsible for hurting you if you have an autoimmune disorder) without taking out the naive and memory T cells (the ones responsible for protecting you).

So, to prove he's not on CRAC, he measures the expression of Kv1.3 and The Other One in all three cell types. And as it turns out, all three cells have fairly low expression of both channels when they're not activated. *yawn*

But! When the naive and memory T cells are activated, they make a whole lot more of The Other One. Effector memory T cells, on the other hand? Make a whole lot more of Kv1.3. That means if you block Kv1.3, effector memory T cells can't function because they don't have enough of The Other One to compensate, and the regular T cells can survive just fine with The Other One.

Dr. Chandy does about fifty thousand more experiments, and they all confirm his hypothesis. Blocking Kv1.3 is a totally awesome idea for fighting autoimmune disorders.

So he goes to the drug companies and asks them to make him a Kv1.3-specific inhibitor. And they all fail. One kills the mouse within ten minutes. One gives it heart problems. Others just aren't specific enough. Come on, drug companies!

Then one day he comes across an article in The Lancet from, like, 1983. This woman with multiple sclerosis was stung by a scorpion. And for about a day, she was kind of sick and all from being stung by a scorpion.

But then? Her multiple sclerosis symptoms went away. For two whole months, she was symptom-free. Or maybe it was two whole weeks. Then her symptoms came back, however.

Clearly, Dr. Chandy thinks, there was something in that venom. So he spends the next few years looking at venomous beasties, trying to find a Kv1.3 inhibitor.

OMG SEA ANEMONE FROM CUBA.

No, seriously. A sea anemone from Cuba. It has this peptide that blocks Kv1.3 like whoa. It's like it was designed to sit right in the pore, held by the four subunits. The modeling they've done is just ridiculous. They know basically every interaction, and so they tack on an extra bit o' stuff to make it even more specific for Kv1.3 in the effector memory T cells. We're talking hundred- and thousand-fold specificity here.

So he starts playing with a mouse model. He gives some mice multiple sclerosis, and they exhibit symptoms and then die. He gives some mice multiple sclerosis, and he gives them this peptide, and they don't exhibit symptoms and then don't die. He can totally keep the mice from progressing to the full-fledged disease. Look, you can even watch the mice yourself, if you have PowerPoint.

Now, so far, he can't magically make the disease go away; he envisions it as an injection once a week or every two weeks for possibly the rest of your days. And he hasn't played with mouse models of the other autoimmune disorders to see whether this peptide could be a beautiful catch-all. But he's hoping for human tests within two or three years.

To sum up, then: intelligently constructed model -> wacky hypothesis -> wackily supported hypothesis -> unsuccessful drug companies -> crazy scorpion story from 1983 -> OMG SEA ANEMONE FROM CUBA -> magical peptide -> wonder drug.

And that is why science is awesome.

Hearts and Minds

I want you to take a look at the cardiac action potential. That right there is why your heart keeps on beating properly.

The action potential is an electrical pulse that stimulates the heart cells to beat. It travels from cell to cell like a Girl Scout selling cookies. When Little Miss Action Potential rings a heart cell's doorbell, though, she really upsets the natural order of things.

You see, a heart cell has a resting membrane potential. If you measured it with an electrode, it'd be negative. That's what you see in Phase 4 on that plot, which is graphing voltage over time.

The action potential makes it positive, and chaos ensues.

First of all, sodium channels open because they're designed to open at a positive voltage, and now sodium ions flow into the cell. Sodium ions, as you may know, are positive. So now the cell is becoming even more positive, as you can see in Phase 0.

"This is crap!" says the cell. Well, not really, because cells can't talk. But what I love about nature is that everything loves balance, everything loves the status quo, and when that balance is upset, it will do its damndest to set things straight.

So before things get too ridiculously positive, the potassium channels open to let potassium ions flow out of the cell. Potassium ions, as you may know, are also positive. Too much positive charge coming in? Simple, shuttle out some positive charge of your own. It's beautiful. It's Phase 1.

Then you have Phase 2, also known as the plateau phase, cause...look. It's a plateau. During Phase 2, sodium, calcium, and potassium ions are all in balance. There's very little inward or outward current here. It's like the channels are all waiting to see who'll make the first move. It's high noon at the Cardiac Corral.

And then Phase 3 hits. A couple very important potassium channels open, like, "The hell with it, the voltage is going back to normal RIGHT NOW." Except they're right on cue. If they were too early or too late, your heart would beat improperly and you would die, and dying is no fun.

All that happens during one action potential. One heart beat. Ion channels opening, closing. Ions going in and out of the cell. All day, every day, 24/7. It's a good thing ions don't get tired. Right now, they just did all that. Oh, look, they just did it again. And again. And again. And—hey, they took a second off. Dude, are you all right?

Dude?

HIV 2: Viral Boogaloo

I'd like to address a few comments on the previous entry. I'll do my best to get to some of the other questions when I have time.

Steph says:

I'm more amused by the people who think HIV can be spread by mosquitos.

If it was easily spread by mosquitos, we'd all have it. All of us.

Sigh. Ignorance.

While some of the links dispelled this myth, I didn't address it specifically in my post because I thought the notion was ridiculous. As Steph notes, if it were easily transmitted by mosquitos, we'd be seeing outbreaks similar to that of the West Nile virus. Mosquitoes pick up the virus from an infected bird. The virus can survive inside the mosquito, and then when it bites a human, it can transmit the virus through the saliva it injects during the bloodsucking.

If you read my previous post, you can see why HIV is not like the West Nile virus. The H in HIV stands for Human. Not hmosquito. It can only survive and replicate in humans. There's also a simian immunodeficiency virus for monkeys. There is a feline immunodeficiency virus for cats. It only affects cats. You can have sex with your cat all you want, and you'll be safe from infection. But not from the fires of hell, you sick, sick man.

In addition, note what the mosquito injects: saliva. HIV does not hang out in the saliva.

What people need to understand is that viruses are just as diverse as human beings. Each one behaves differently, and just because one can be spread one way doesn't mean another can be spread that same way. We try to teach our children not be prejudiced against other people, but I think viruses deserve the same respect. Come on. Don't judge a virus by its capsid.

Actually, you might want to judge a virus by its capsid, nevermind. But don't judge a virus by its...being a virus.

Stephanie says:

Definitely some information that needs to get out there...have you heard that some of the abstinence-only sex ed courses teach that you can (apparently easily) get AIDS from tears?

This kind of thing makes me want to cry. And then look at my tears that would not have HIV in them were I infected.

Steph (aka Nonian) asks:

Since this is sort of related to your post, here's my most recent HIV question. I heard recently (maybe from CNN?) that we are very close to eliminating infant HIV in the US. I had the impression from the article that most of this is from early testing and administering drugs (not sure if the drugs go to the mom or baby) that prevent the passing of the HIV prior to and during birth. I have no idea how this would work, but I can sort of see how it might be possible.

However, the piece when on to say that there are also drugs that you can give to the infant once they have HIV in their system that will prevent the infant from getting (or maybe keeping?) HIV. Is this possible? If it is, why can't you do the same for an adult?

An HIV-infected mother has about a one in four chance of passing on the virus to her child. This is called vertical transmission, as if you were looking at a family tree, the virus would be traveling vertically, from one generation to the next. Sexual intercourse is, appropriately, a form of horizontal transmission, for similar reasons.

The virus may be passed on during the gestation period, since there is blood traveling from the mother to the baby, but there is a much higher risk during delivery due to the ruptures of various membranes. Anyone who's seen a baby being delivered knows there's a lot of blood involved. For this reason, cesarean section is quite effective in and of itself at reducing HIV transmission.

In recent years, what has also helped is a drug regimen. We have several anti-retroviral drugs available now in addition to the headline-making AZT. These drugs block the protein HIV needs to replicate. Note that the previous sentence did not involve the virus dying.

The pregnant woman is given anti-retroviral therapy (ART) after the first trimester until the baby is born. This reduces the viral load. If there's less of the virus floating around, there's less chance of any getting into the baby. Plus, since the drug gets passed into the baby as well, any virus that does make it into the child won't be able to replicate and infect.

After birth, the newborn gets ART for six weeks to prevent the virus from getting its figurative claws into its immune system. Unfortunately, the mother shouldn't breastfeed, since there's chance of more virus transmission.

The reason, I think, we're so excited about this is because A) everyone loves babies and B) it's easy. There is exactly one way a baby is going to get HIV, and it's from the mother. Identify the source of the virus and stop it. Simple.

Why, then, can't we do the same for an adult? Well, theoretically, we can, I suppose, if you want to pay the thousand dollars for AZT in exchange for a night of unprotected sex. And that wouldn't really work the same as a morning after pill because remember, the infected person would not have had their viral load decreased.

It's difficult to get these kinds of studies done, as you may imagine. To test the effectiveness of ART as a preventative measure, you have to get healthy test subjects to engage in unprotected sexual intercourse with HIV-infected subjects. And then give the subjects ART and see how many of them breathe sighs of relief and how many of them become infected in the name of science.

They're doing studies in Brazil, and the data look okay, but not phenomenal. No one seems to be convinced that post-sexual-exposure chemoprophylaxis (PEP)—whoa, whoa, let's break that down. post = after, sexual exposure = sexual exposure, chemo = chemical, prophylaxis = protection (remember that the fancy name for condom is prophylactic). so all those syllables mean, "chemical protection after exposure to the virus through sexual contact"—is truly effective, but that doesn't mean people won't try it. This could potentially be very bad, because it may encourage more unsafe sex and lead to even more infection.

And even after all this, there is the one word that strikes fear into the hearts of virologists everywhere: resistance. There are already AZT-resistant strains of HIV floating around.

We don't have a cure, folks. These drugs are the best we have. Let's make sure we have to use them as infrequently as possible.

You Can't Get AIDS from a Sneeze

My latest article is about aromatase inhibitors, a new class of breast cancer drugs, but a far more interesting article in today's science page is on Bexxar, a lymphoma drug that actually uses antibodies to administer radiation specifically to cancer cells.

A couple days ago, I read about someone whose health teacher didn't hang around with gay people because she was afraid she might catch AIDS. I didn't know what to say. I couldn't believe there were people so ignorant, yet it didn't surprise me. I will counter this ignorance by spreading knowledge, and I expect you to spread it yourself. Go on. Be a virus.

Diseases are spread by pathogens. These are any number of microscopic buggers: bacteria, viruses, fungi, etc. AIDS is caused by HIV, which is Human Immunodeficiency Virus.

Now, there is some controversy as to whether a virus can truly be considered alive, but for my purposes, I will consider it to be a living organism. It contains genetic information and the ability to pass it on. That's good enough for me. Also, it allows me to anthropomorphize it more easily.

Each virus is different. They like different parts of the body. They require different things to survive. From what I've learned, I'm not even certain we know why certain viruses behave the way they do, but we know they do, and that's what's important.

HIV is found in high concentrations in the blood, semen, vaginal fluid, and breast milk. These are the only bodily fluids you really need concern yourself with when worrying about "catching AIDS." It is present in very low quantities (if at all) in the saliva, sweat, tears, feces, and urine, but the concentration is so low as to be negligible (we're talking ten thousand times lower than in the blood). A person with AIDS — let's call him Bill — could pee directly into your mouth and you'd be safe. But that's really gross.

The other thing about HIV is that unlike the cold and flu viruses, it can't survive outside the body for very long at all. It's incredibly weak, and very codependent. HIV is hardly present in mucus in the first place, so a cough or sneeze spells a very lonely death for the virus. By the time it reaches you and scrambles around looking for a way to get in your nice warm body, it's too late.

That is the other consideration: the virus needs a way to get into your bloodstream. If Bill touches you, there is no way HIV from inside him could have gotten into your blood. You are safe. First of all, there was very little virus hanging out on his hand anyway. Plus, HIV is incredibly lazy, and it needs easy access. None of this epidermis business.

If Bill — no, let's switch gears and talk about his friend Karen — If Karen bleeds on you, you are also safe. Wash it off immediately, but don't flail around screaming, "I've got AIDS! I've got AIDS!" Like the process required to become a vampire, the blood needs to mix with your own. This is why blood transfusions sometimes led to HIV infection — now that we have HIV tests, it's less of an issue. In the same vein — no pun intended — sharing needles is another method of transferring the virus from infected blood to fresh blood.

The fact that HIV is so concentrated in the semen and vaginal fluid is why it is a sexually transmitted disease. During sex, the vaginal lining can be sloughed off, providing a route to the bloodstream. The reason gay men have a high rate of affliction is because the rectal lining is even thinner than the vaginal lining. You have the two conditions necessary for infection: a large supply of virus and a way to get in.

Every virus is different, and these are the quirks of HIV. It takes quite a bit of work to get, as direct access to the bloodstream is not very common. Plus, only certain bodily fluids carry a high risk of infection.

And of course, even after all that, you don't contract the disease immediately. The virus can party in your body for years before getting to work. All that time, though, you're able to pass it on.

The A in AIDS stands for Acquired. You cannot just magically get HIV; you must acquire it from someone else. You can have unprotected sex with three thousand people, and if none of them have the virus, your chance of having the virus is zero. Unless you already had it, in which case you have a lot of phone calls to make.

AIDS is a sexually transmitted disease. It is transmitted through sex. It is transmitted through direct blood-blood contact. You can't get it from a sneeze. Or a cough. Or a touch. And for God's sake, you can't get it from being around someone with AIDS.

If you know someone with AIDS, here are some things you probably shouldn't do with them:

• have unprotected sex
• take a blood oath
• share needles
• remove some of their blood with a syringe and inject it into yourself

If you know someone with AIDS, here are some things you should do with them:

• give them a hug
• shake their hand
• kiss them
• share your drink

It is literally safer to be around someone with AIDS than it is to be around someone with a cold. If the person with AIDS has a cold, though, watch out! You might get sick!

With a cold. Not AIDS.

Here are some informative pages on HIV transmission:

• CDC Fact Sheet
• Minnesota AIDS Project
• Avert.org

Honestly, if you meet someone who doesn't understand how HIV is transmitted and why, please set them straight.

Epidemics Can Induce Genetic Change

Scientist finds surprising links between arthritis and tuberculosis.

Included in this article is a bonus: the definition of "drug target." Because while you know the word "drug" and the word "target," putting them together causes them to lose all meaning. Lost in the editing room was the definition of another term with similar properties: "animal model." An animal model is a laboratory animal that has been given a disease of interest. By studying the disease — and the effects of drugs on it — in the animal, scientists can better understand the disease in humans.

alliterator asks:

"Here's my question: have you heard of the prion protein which causes the disease kuru and CJD (also known as Mad Cow Disease) and its relevance to the fact that perhistoric human civilization had widespread cannibalism?"

I have heard of prions, but I had never heard it related to prehistoric cannibalism. That's very interesting.

The funny thing about prions is they're infectious proteins. Normally, when you think of infection, you think of bacteria and viruses. Bacteria and viruses have nucleic acid, genetic material with which they can replicate and infect new cells. But a protein has no nucleic acids: it's made up of amino acids. It has no ability to replicate.

Instead, these rogue proteins seem to travel from cell to cell converting normal proteins into prions (not any protein, only the prion protein PrPC). And just like a viral infection, eventually the excess of prions causes the cell to die and release the infectious material into the open, where the disease can spread.

The initial prion is very much like a cult leader, travelling from city to city brainwashing new recruits. The recruits in turn spread the message.

I would like to look up more about prions and their relation to cannibalism, but until then, here are some useful sources for background information:

All About Prions

Prion Diseases

Prions: Puzzling Infectious Proteins

Do Prions Exist?

Protein Synthesis

And thus Protein Angst was born.

This is the blog of an aspiring science writer, a man who forsook a Ph.D. for a career in interpreting science for the layperson. Here, he seeks to reach those laypeople, to talk about science in a way they can understand. He will attempt to do this with clarity, accuracy, and frequently, humor.

Usually, he will use the first person.

My first entry here will be a short tirade on the difference between pharmacy and pharmacology. Throughout college, I was plagued with the response to my answer to the question, "What are you majoring in?" I said, "Biochemistry and English," and, nine times out of ten, I heard, "Interesting combination." Those two words, over and over. When I went to graduate school, I thought those days were behind me, but no. Now, the exchange goes like this:

"What are you studying?"
"Pharmacology."
"Oh, so you're going to be a pharmacist?"

Pharmacology is not pharmacy. I don't care that they begin with the same seven letters. So do "Michael Jackson" and "Michael Chabon."

Pharmacy is defined as "the art and science of preparing, compounding, stabilizing, preserving and dispensing medications and the provision of drug and related information."

Pharmacology is defined as "the science of the action of drugs and other chemicals on living biological systems."

There is a major difference here. Pharmacy is all about drugs, and little pills, and what color they are, and about three thousand other things about the actual medicine that people take.

Pharmacology, on the other hand, is about what that medicine actually does to people inside, and, more importantly, what's going on inside those people to begin with. A pharmacologist learns about organ systems, and the interactions between cells, and the metabolism of drugs. He works to develop new understanding of the mechanisms within the body, understanding that can lead to better, safer medicine.

Pharmacology != Pharmacy.

Now that I've cleared that up, the floor is open. Feel free to ask questions at any time. My background is in biosciences, so I'm much more likely to be able to answer those sorts of questions, but I will do my best. Don't ask me your homework questions. That's cheating.

From time to time, of course, I will just wax eloquent on the wonders of mitochondria, the treachery of cytochrome c, and the use of DNA evidence in Miss Congeniality.

And to prove I know what I'm doing, here's my very first article, published in the Michigan Daily.