What are oncogenes?

I’m trying to raise money for the The Leukemia &amp Lymphoma Society, and I promised to do a few things if we reached certain goals. I said I’d write a post explaining what oncogenes are, while wearing a pirate hat, if we raised $2500. So here you go, arrr.

madpiratemyers

If you want more, go to my Light the Night fundraising page and throw money at it. I’ll write the next part when we hit $5000. Note that we’re also getting matching funds from the Todd Stiefel Foundation, so join in, it’s a good deal.

Cancer is not a creative, original disease; it has not been honed by ages of evolution to craft novel lines of attack on your body. Instead, it’s an opportunistic thief. Cancer misuses and perverts existing processes in your cells to send them out of control. Everything cancer does is simply the same thing your cells normally do, only amplified and unconstrained, driven by damage to the genes that would normally regulate their behavior.

Here’s a metaphor, a car with a dangerous defect. It has acquired a glitch in the accelerator so that every time you start it up, it immediately roars up to full speed, as if you’d floored the pedal. The problem hasn’t created anything new in the car, it’s just taken something you normally need to do, that is, regulate the speed of the machine, and stripped you of all ability to control it. That’s what an oncogene does; it is a gene that is normally involved in controlling the rate of cell proliferation, for instance, and a mutation has broken it in such a way that it now tells the cell to divide as rapidly as possible.

Now if you were driving down the freeway and suddenly your accelerator were stuck and you couldn’t slow it down, you’d have alternative strategies to stop (and so does the cell). You could hit the brakes or shift gears or turn off the ignition key. Cancers acquire another set of mutations that destroy the ability to shut off cell processes, analogous to breaking the brake pedal or snapping off the gear shift handle. These genes that can block the effects of out-of-control cell regulators are called tumor suppressors, and I’ll write about those at another time. Today I focus on oncogenes, regulators of the cell that must be damaged by mutation to produce an excessive response.

The first concern that comes to everyone’s mind is that you don’t want to have your cells running amuck — no one wants cancer. Just as you can do your best to maintain your car, you can also live sensibly — eat in moderation, avoid carcinogens or other behaviors that expose you to radiation, and get regular checkups — to reduce the likelihood of deleterious mutations. But they can happen anyway, through no fault of your own. Every time your cells divide, there is a very small chance of an error in replication that inserts a mutation into an oncogene. Just existing, even while doing everything exactly right to maximize your health, brings with it a base chance for a mutation. Given normal rates of cell division, every single one of you reading this is going to acquire about 20,000 DNA lesions today and every day. Almost every one of them will be patched up by DNA repair mechanisms (you have no idea how important DNA repair is to your continued health), but even so, one will occasionally slip through — over your lifetime, your cells will acquire an estimated 10,000 mutations. Live long enough, playing these odds, and cancer is essentially inevitable.

So cancer is fundamentally a chance process. There is no reason people get cancer, no purpose behind it, and everyone is susceptible. Some behaviors can increase the odds — smoking, failing to use sunblock — and you can also inherit genetic predispositions that increase the likelihood of acquiring a full set of mutations that lead to cancer, but ultimately, no one is at fault for cancer.

So what can go wrong? The diagram below is a simplified illustration of the various signaling networks in the cell. These are some of the pathways by which cells are told to regulate their behavior.

signalingnetwork

I’m going to focus on just the greenish box in the middle, the one labeled “Proliferation Circuits”, just to keep it simple. Think of that as the accelerator peddle for your cells. Sometimes your cells need to be encouraged to proliferate. For example, during childhood there are general signals to encourage stable patterns of growth, and during adolescence there may be novel hormonal signals to encourage new growth of selected populations of cells. If you’re injured, local growth factors are secreted to encourage cells to divide and repair the damage. So that’s what you’re seeing on the far left: growth factors and hormones can send a signal to the cell to give it permission to grow.

In order for a signal to be received, the cell has receptors on its surface that can bind to the growth factors and hormones. When a receptor binds to a signal, it changes to send a signal to other proteins (all those green circles) inside the cell. Think of it as like a doorbell; growth factor comes calling, presses the doorbell/receptor, the bell rings/sends a chemical signal into the interior, all the proteins get busy.

You can probably imagine how this system could get broken already. What if the receptor were damaged in such a way that it constantly sent a signal inwards, even if no growth factor were present (this is called becoming constitutively active)? What if one of the internal proteins were damaged in such a way to become constitutively active, so that it acted as if it were seeing the receptor as bound to a growth factor, even if it wasn’t? Now the cell is being constantly lied to by its sensory apparatus, and behaves as if it were being constantly told by the body to divide and divide and divide — it is on the road to being cancerous.

Let’s look a little bit closer at that pathway and give some of those green balls a name. This is the Ras-Raf signaling pathway.

ras-raf

It’s a bit Rube-Goldbergian, but hey, that’s biology. In the top left corner you see something called EGFR, short for epidermal growth factor receptor. That’s our doorbell; the asterisk after the name in this diagram means that you see it mutated fairly frequently in human cancers. The box explains that it is seen to be damaged in 10-20% of certain kinds of cancers; when it’s mutated, it acts as if its signal, TGFα (Transforming Growth Factor Alpha) is always present. EGFR may also be perfectly normal, except that it is overexpressed, that is, present in a far greater number of copies on the cell surface, which makes the cell particularly sensitive to tiny quantities of growth factor. This happens even more frequently in many cancers.

The next steps in the pathway involve switching on Sos/Grb2, which activates Ras (look at the box; Ras is very commonly mutated in a great many cancers), which activates Raf, which activates MEK, which activates ERK, which promotes DNA replication. This is called a signaling cascade, and these kinds of sequences are all over the place in the cell. The advantages of this pattern is that many steps can be amplification steps, where one activated protein switches on many copies of the next protein in the sequence, and also each step is an opportunity for regulation.

Now be strong: I’m going to look even more closely at a key oncogene, Ras. Ras is important; it’s a central regulator of proliferative processes in the cell, and it is commonly one of the proteins made constitutively active in cancers.

ras

How is Ras switched on and off? In order to be active, Ras needs to be bound to a small molecule called GTP, guanine triphosphate, a base with three phosphate groups attached to it. It must be three; anything less, it isn’t active, so if it is bound to GDP, guanine diphosphate, it is inert. When it is bound to GTP, Ras changes shape to open up a binding site that can dock with the next protein in the chain, Raf, and activate it in turn.

Ras is switched on by the previous protein in the chain, SOS. SOS is a guanine exchange factor, and from the name, you can guess what it does: it swaps out the stultifying GDP molecule from Ras and replaces it with the energizing GTP molecule. Which allows it to bind with Raf, which then activates MEK, etc.

What switches Ras off? Ras is also an enzyme, specifically a GTPase — it cleaves its own GTP into a GDP. It turns itself off! What this means is that it acts as a kind of momentary switch. When a growth factor molecule arrives at the cell, Ras will respond by briefly initiating the cell division machinery, and then shutting itself down. It needs a sustained signal to keep cell division humming — a little triggering flicker of a random molecule bumping into the cell is not enough. This makes a lot of sense for cell cycle control. Ras is a reluctant activator, always hesitating and drawing back, and it needs constant prodding from external signals to keep doing its job.

Except when it’s mutated.

The most common cancer-inducing mutation in Ras is a single amino acid change in the 12th codon of its gene that greatly reduces the effectiveness of its GTPase activity. It binds GTP, becomes active, and then does not cleave the GTP — it clings to it instead. It switches from being a reluctant activator of cell division to instead being an avid, hyperactive activator — any transient signal, even a bit of noise, becomes an excuse to tell the cell to start dividing madly.

And that’s the beginning of a cancer, a rogue protein, made by an oncogene, that’s telling the normal, healthy cellular machinery to do its thing when it shouldn’t.

There’s much more to cancer than that, of course — cancer is more than just excessive cell division, and also the cell has many fail-safes, the tumor suppressor genes, that are supposed to put the brakes on when renegade proteins are going wild. But — oh, and this is cruel of me — to hear that part of the story, you’ll have to donate to my Light the Night fundraising page. When we get to $5000, I’ll tell you all about tumor suppressors.


Croce CM (2008) Oncogenes and cancer. N Engl J Med. 358(5):502-11.

Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646-74.

Hesketh R (2013) Introduction to Cancer Biology. Cambridge University Press.

The New Age can be as deadly as Catholic ignorance

Read this story about abortions: it’s not anti-choice. It’s anti-science and anti-medicine. It’s appalling. She contrasts brutal “Western Science” with its machines (and also its caring people: ignore her colorful descriptions of the technology, and her experience with people in the abortion clinic was one where she was asked if she was sure she wanted it, and a woman who tried to help her afterwards) with “natural healing” in which she takes a few gentle herbs and just visualizes shedding the walls of her uterus, and magically her pregnancy disappears.

Then she babbles about how it is just fine if the “fundamentalist dickheads” burn down all the women’s clinics, because they’ll just be able to use organic natural herbal chemical-free machine-free medicine-free abortions using the magic power in women’s heads.

Jesus.

This is one of the nice things about FtB. Now you can go read Miri as a warm-up, finding parts of the essay that are worthwhile, while others suck.

Then go read Avi’s total destruction of the dangerous anti-medical quackery in the story.

It’s all good.

Thanks, M.D. Anderson, for adding another confounding variable

I’ve been talking to my class this week (and it’s going to be a theme next week) about the difficulty of analyzing epidemiological data on cancer — that there are so many steps to cancer progression and so many environmental and genetic inputs to the disease that sorting them all out is extremely complex. What I haven’t mentioned yet, but definitely will now, is the factor big money plays in encouraging statistical fraud.

The University of Texas MD Anderson Cancer Center in Houston has been the top-ranked cancer center on US News & World Report’s best-of list for the past 7 years. But that top ranking was aided by a massive error in data used to evaluate its care.

The error in M.D. Anderson’s favor was made by–M.D. Anderson! Avery Comarow, who assembles the rankings at U.S. News, told The Cancer Letter that this was a huge "screw-up." The hospital systematically misclassified emergency patients, which led to the exclusion of nearly 40 percent of admissions, Paul Goldberg, The Cancer Letter’s editor, reported. He said the error was discovered in 2009, but no way could be found to correct it. "Since U.S. News averages data over three years, the results of the M.D. Anderson top rating by the magazine released July 16 are still partially based on tainted data," he wrote.

Is “error” actually the right word to use?

Forest for the trees…

Something that really, really annoys me is reading a paper discussing a rich and complex data set in which the authors squink their eyes tightly and use statistics to zoom in and stare fixedly at one parameter. It happens all the time. It’s as if some scientists think it’s a triumph to reduce a phenomenon to one single simple cause, rather than appreciating the diversity of inputs.

The latest example is a study pegging yet another medical procedure as the cause for autism, in this case, early induction of labor and augmented delivery. Autism is probably a perfect target for these kinds of silly approaches; it almost certainly has a wide range of contributory causes, and it’s always a mystery to the parents of affected children, who look for answers. It’s the vaccines, they say. No, it’s the drugs we took during pregnancy. No, it’s the doctors who did funny business in the delivery room.

Fortunately, we’ve got Emily Willingham to actually look at the forest.

When she looks at the data, she finds that the authors are right, that there’s a correlation: if a mother gets both induction and augmentation, there’s a 27% increase in the chance that the child will later be identified as autistic.

What they don’t tell you is that the same data set shows that having a college-educated mother increases the odds of autism by 30-33%. And that smoking during pregnancy decreases the chance of an autism diagnosis by 14%.

Wait, stop! If you’re pregnant, don’t take these numbers as an indication that you need to start watching more Glenn Beck to make yourself stupider, and that you need to take up a tobacco habit. You’re looking at the tree again and ignoring the forest. What these correlations suggest is that we should be looking into some property of the population that unites them — that each one in itself is not necessarily causal, but that they are common symptoms of the true link. We need to see the big picture to puzzle out the answer.

And sometimes interpreting the phenomenology of a single parameter analysis would lead to a bad result: I can pretty much guarantee you that being a heavy smoker during pregnancy is much worse for the fetus than non-smoking.

Willingham does see the bigger picture.

This study didn’t show that induction or augmentation during childbirth substantially increases the risk for autism, although it hints at a greater influence of socioeconomic status and by implication, healthcare access. If anything, based on earlier literature, it adds a slight if only mathematical confirmation of the perception that births involving autistic children can be associated with more complications, such as the presence of meconium, gestational diabetes, and fetal distress, than births involving non-autistic children. And that points to induction and augmentation as useful in these situations, not as problematic, and certainly does not affirm them as a risk.

Oh, look, it’s practically a jungle!

But what about the baaaaabies?

Nicotine is a teratogen — it’s known to have all kinds of interesting effects on the developing fetus. It’s very strongly associated with low birth weight, increases the likelihood of premature placental detachment, and it also causes deficiencies in lung development. You shouldn’t smoke during pregnancy (or use nicotine patches or any of the other alternatives for nicotine delivery), and if you really, really care about babies, you shouldn’t encourage other people to use nicotine during pregnancy.

Isn’t Jenny McCarthy supposed to be really passionate about protecting children? I recall her getting rather shrill about those wicked vaccines with their traces of propylene glycol used as a preservative.

Forget that, though, when money is on the line. Jenny McCarthy is now shilling for e-cigarettes…which use propylene glycol as part of a delivery system for nicotine.

So…in Jenny McCarthy’s mind, vaccines, which have been proven safe and even better, prevent serious diseases, are evil; e-cigarettes which give you a jolt of a known teratogen and toxin are sexy and fun.

As a reward for her hypocrisy and child-killing opinions, she gets a cushy job on broadcast television.

Cystic Fibrosis is all your fault

Cystic Fibrosis is a serious genetic disorder caused by the inheritance of a defective transporter protein. It leads to an accumulation of mucus and fluids in the lungs that can cause progressive scarring and damage to the tissue, and eventually loss of so much lung function that respiration is inadequate, and the victim dies. It’s a terrible disease, and it’s in the news today because a ten year old girl just received a lung transplant to deal with CF.

If you want to learn more or do more, read the Cystic Fibrosis Foundation website. That’s a reasonable source of public health information.

But do not read the Guardian Express.

The Guardian Express has published an article that suggests lung transplants aren’t the best option for CF. I just want to say…lung transplants are a last-ditch effort when no other recourse is available; nobody would suggest casually getting a transplant when other precedures are available for amelioration and maintenance. You get a lung transplant when your lungs are on the verge of failing to function.

So this article is talking nonsense from the title onwards. And then you discover why they’re arguing against transplants.

The problem is, after receiving a lung transplant, the new lungs do not have CF, but Cystic Fibrosis still exists in the sinuses, pancreas, intestines, sweat glands and reproductive tract, which may find their way to the new lungs eventually.

Let that sink in. CF is a genetic disease. This article is giving out medical advice, written by an author who thinks genes migrate out of the sweat glands into the lungs.

And what does this author suggest in lieu of a transplant? Oregano oil, yoga, rubbing essential oils on your skin, and herbs.

You may be thinking this all sounds terribly ineffective in the face of a disease that destroys the tissues of the lungs. But you’d be wrong. It’s an emotional disease, believe it or not.

According to metaphysics and those who study the relationship between our emotions and the body have found a correlating belief for nearly every physical manifestation in form. Often these beliefs are passed down to us from our parents and we aren’t even aware we are carrying them. In those with what is known as cystic fibrosis, this could be the case – as more often than not, individuals are born with this condition.

Louise Hay, a famous proponent for linking emotional causes to physical ailments has written several books on the subject (You can Heal your Life; Heal your Body) after healing herself from serious health problems by addressing her thoughts and emotions. The correlation she places for those suffering with cystic fibrosis is that they have a ‘thick belief that life won’t work for them.’ In order to combat or heal this belief, she offers the daily affirmation: “Life loves me and I love life. I now choose to take in life fully and freely.” If this is a condition you or someone you love is dealing with, perhaps it would be beneficial to look at the emotions behind the dis-ease. We are a whole being, not just a body, and when we can address our problems more holistically we have a greater chance at success.

Holy crap … I thought the article was a solid wall of garbage until that point, but when they stoop to victim blaming and telling people that cystic fibrosis is a “choice”, I suddenly find myself sympathizing with those people who believe in a Hell, because I want this person to go there.

But don’t worry! They include a disclaimer at the end!

(Information in this article is not intended to diagnosis, treat or cure and is not medical advice, but rather the researched opinion of the journalist. Please discuss options with your health care professional)

The article is full of medical misinformation and medical advice. The disclaimer fools no one, Stasi Bliss, you ignorant fraud.

It’s not just this one author, though. The Guardian Express regularly publishes tripe, such as this one about “Organ Transplants Cellular Memory Proves Major Organs Have Self-Contained Brains?”.

Organ transplants cellular memory is a premise which exemplifies that our brain is not the only organ that stores personality traits and memories because major organs may have self-contained brains. This is not a new theory because imaginative writers have already written about this concept in the 17th century, which is long before organ transplants were even believed possible.

In our modern culture, cellular memory was first studied in heart transplant recipients when the patients displayed strange cravings, change in tastes, cravings and mild personality. Major organs like the heart, liver, kidney, and even muscles are known to contain large populations of neural networks, which are self-contained brains and produce noticeable changes. Acquired combinatorial memories in organ transplants could enable transferred organs to respond to patterns familiar to the organ donors, and it may be triggered by emotional signals. Science discovered evidence that nervous system organs store memories and respond to places, events, and people recognized by their donors.

When your ideas are supported by 17th century fiction, you have a problem. They do cite one contemporary source: Gary Schwartz, the life-after-death charlatan from Arizona.

Anti-vaxxers are as bad as creationists

In Australia New Zealand:

It started when seven-year-old Alijah got a small cut on the bottom of his foot in December 2012.

"Of course we didn’t think it was too serious, it was just a little cut but a couple of days later he started getting symptoms like a stroke on the side of his face," Mr Williams says.

"A couple of days later during the night he started to get cramps across his face. His face would contort and he was in a lot of pain."

After 24 hours in Auckland’s Starship Children’s hospital, the doctors diagnosed Alijah with tetanus, and he was taken to intensive care.

His parents didn’t get him a tetanus shot because they were afraid of vaccines.

In California:

Whooping cough, also known as pertussis, has claimed the 10th victim in California, in what health officials are calling the worst outbreak in 60 years.

Since the beginning of the year, 5,978 confirmed, probable and suspected cases of the disease have been reported in California.

All of the deaths occurred in infants under the age of 3 months, says Michael Sicilia, a spokesman for the California Department of Public Health. Nine were younger than 8 weeks old, which means they were too young to have been vaccinated against this highly contagious bacterial disease.

"This is a preventable disease," says Sicilia, because there is a vaccine for whooping cough to protect those coming in contact with infants, and thereby protect the infants.

However, some parents are choosing to not vaccinate their children. In other cases, previously vaccinated children and adults may have lost their immunity because the vaccine has worn off.

Ignorance kills, and we’ve got people promoting ignorance.

People like Robert F. Kennedy Jr.

Robert F. Kennedy Jr. likes to talk. When he calls you to discuss vaccines, he talks a lot, uninterruptably. He called Keith Kloor after Kloor wrote a story for Discover about RFK Jr.’s keynote address to a convention of people who think vaccines cause autism. You can read about their conversation at Kloor’s blog. Phil Plait wrote a story about RFK Jr. for Slate last week, pointing out that the idea that vaccines cause autism is a crackpot theory that has been thoroughly debunked, that it is dangerous, and that RFK Jr. is one of its most effective proponents.

Kennedy claims that thimerosal, a preservative used in some vaccines, causes autism. No, it doesn’t. This has been tested out the wazoo, and there’s no connection between autism and thimerosal, or autism and vaccines, for that matter. In order to back up his claim, Kennedy is reduced to completely misrepresenting the scientific evidence.

For a guy whose family has such a distinguished record of public service, Kennedy says some pretty awful things about government employees: “The lies that you are hearing and printing from the CDC are things that should be investigated.” He spoke to one scientist (he named her but I won’t spread the defamation) who, he said, “was actually very honest. She said it’s not safe. She said we know it destroys their brains.”

I asked the scientist about their conversation. She said there is in fact no evidence that thimerosal destroys children’s brains, and that she never said that it did.

There’s a pattern here.

When RFK Jr. challenged the university scientist about a study of the biological activity of thimerosal in vitro, which “everybody accepts because journalists hadn’t read it,” the scientist said, “ ‘Oh, yeah, you’re right about that.’ He backpedaled.” That’s because “now he was dealing with somebody who wasn’t afraid to read science.”

I talked to the scientist, who would prefer I not use his name because he gets death threats from unhinged anti-vaxxers. He said, “Kennedy completely misrepresented everything I said.”

I don’t know why Kennedy is bothering to misquote scientists and trying to get scientific authority to back him up, though, because he doesn’t believe in scientists anyway. He’s got a gigantic conspiracy theory in which all these scientific organizations are lying.

Robert F. Kennedy Jr.’s elaborate conspiracy theory is just as delusional and dangerous. Rather than accepting the findings of the Institute of Medicine, the National Institute of Mental Health, or the American Academy of Pediatrics, Kennedy says the scientists are lying. He says vaccine-makers are intentionally poisoning kids and giving them autism. Only he and his fellow activists know the truth because journalists, although they may report aggressively on the National Security Agency, Defense Department, and Central Intelligence Agency, are cowed by the Centers for Disease Control and Prevention.

Apparently hereditary political lineages are a really bad idea. The UK has Prince Charles, and the US has Robert F. Kennedy Jr.

Angeline Jolie just became an even more interesting person

Wow. Jolie is a beautiful woman who makes a living as an actress, where looks can be important, and she discovered that she carried an allele of BRCA1 that puts her at a very high risk of coming down with breast cancer sometime in her life. She looked at her situation rationally — she is an atheist after all — and made the decision to get a preventive double mastectomy. She chose to maximize her chances of living a long life over preserving a secondary sexual characteristics.

That’s strong and smart. She hasn’t lost anything of any importance.

Jolie also took an important next step and came forward with the news to encourage other women to make good choices.

I choose not to keep my story private because there are many women who do not know that they might be living under the shadow of cancer. It is my hope that they, too, will be able to get gene tested, and that if they have a high risk they, too, will know that they have strong options.

Life comes with many challenges. The ones that should not scare us are the ones we can take on and take control of.

The only glitch in this story is that this is America: if you’re not a mega-millionaire movie star, you’re not likely to be able to afford the expensive genetic testing, or the extensive surgeries. But maybe Jolie’s openness will encourage politicians to correct that, too.