Should you circumcise your child?

Probably not. But the New York Times reports:

A review of studies has found that the health benefits of infant male circumcision vastly outweigh the risks involved in the procedure.

Actually, it doesn’t. Not at all. The paper is all about the frequency of circumcision in the US; this is the only real data in the paper, and notice that a good chunk of it is speculation.

Prevalence of adult circumcision in the United States during the past 6 decades (1948-2010). The solid line represents documented prevalence among adults; dashed line, [Morris's] predictions.

Prevalence of adult circumcision in the United States during the past 6 decades (1948-2010). The solid line represents documented prevalence among adults; dashed line, [Morris's] predictions.

It does toss in a table purporting to show the tremendous risks of not circumcising baby boys, but this is not new — these are the same sloppy data that the author has been peddling for over a decade. With some trepidation, I give you a sample from his 2007 paper: don’t trust these numbers!

circrisks

The author is Brian Morris, better known as the Man Who Hates Foreskins. He’s a real crusader, who touts foreskin removal as just as important as vaccination — that leaving it intact imperils the child to a 1 in 3 chance of a serious condition requiring medical attention. You might immediately question how he arrives at this conclusion — by multiplying a series of dubious assertions together — and the likelihood of it being true, given that circumcision is a culturally variable practice, and that countries where it’s rare (for instance, in Scandinavia, where the frequency of circumcisions is around 2%) don’t typically have emergency rooms crowded with young boys whose penises are in painful, infected, states, raddled with disease.

I suppose it could be because glorious Scandinavian penises are perfect and universally wholesome — that’s what I’ve been told, anyway — but that would be baseless speculation and unwarranted extrapolation of anecdotes into unsupportable evidence, of the sort that Brian Morris does.

Take that first condition, the likelihood of urinary tract infections. That’s taken from a sample of 36 children, half of whom had an unknown circumcision status, and the difference was not found to be statistically significant. Yet here he just presents it as established fact, that uncircumcised children have a ten-fold greater rate of urinary tract infections.

Or look at his claim of much greater rates of HIV infection. There actually is some interesting mechanistic reasoning behind that: the foreskin represents an enlarged area of delicate membrane which could be an avenue of entry for some viruses. But the real test would be an epidemiological study: there are lots of circumcised men around, and lots of uncircumcised men, when we look at the rates of infection, is there a significant difference? It hasn’t been done very often, but when it is, the hypothesis often fails to be supported. Here’s one example of a scientist who thought heightened sensitivity to STIs was a reasonable hypothesis (his “hunch”), but found it didn’t pan out at all when examined.

Armed with this hunch, rather than set up a website I chose to do some research. Australia is a good place to do such research because there is a roughly even population split for the intervention (circumcision) and in most cases it is not a maker of ethnicity, wealth, education or religion. Unexpectedly, our research findings were uniformly negative. Circumcision did not protect against STDs in our clinic population, though we did not look at HIV because it is rare in heterosexual men in Sydney.

Then there are some of Morris’s very peculiar ideas. This is the abstract from a paper advocating more circumcision; note that one of his arguments is basically that women find uncircumcised penises ugly. As usual, no evidence for that is presented.

Circumcision of males represents a surgical “vaccine” against a wide variety of infections, adverse medical conditions and potentially fatal diseases over their lifetime, and also protects their sexual partners. In experienced hands, this common, inexpensive procedure is very safe, can be pain-free and can be performed at any age. The benefits vastly outweigh risks. The enormous public health benefits include protection from urinary tract infections, sexually transmitted HIV, HPV, syphilis and chancroid, penile and prostate cancer, phimosis, thrush, and inflammatory dermatoses. In women circumcision of the male partner provides substantial protection from cervical cancer and chlamydia. Circumcision has socio-sexual benefits and reduces sexual problems with age. It has no adverse effect on penile sensitivity, function, or sensation during sexual arousal. Most women prefer the circumcised penis for appearance, hygiene and sex. Given the convincing epidemiological evidence and biological support, routine circumcision should be highly recommended by all health professionals.

I suspect that women’s preferences are going to be shaped by culture, by familiarity, rather than some objective hideousness of the foreskin, and what the heck is appearance doing in a paper that is supposed to be summarizing medical evidence, anyway?

It’s also an argument that can cut both ways. When presented with evidence that one phenomenon, dyspareunia (painful intercourse) was found to be more common in partners of circumcised men than uncircumcised men, Morris waved it away by arguing that women in countries with lower rates of circumcision might be disturbed by the sight of a cut penis.

Morris et al. should be commended for their creative attempt to dismiss the higher prevalence of frequent dyspareunia in women with circumcised (12%) than uncircumcised (4%) spouses (ORs between 4.17 and 9.00). They suggest that Danish women with circumcised spouses may be so psychologically troubled by the shape of their spouse’s penis that it might result in painful intercourse. A more plausible explanation would be that reduced penile sensitivity may raise the need among some circumcised men for more vigorous and, to some women, painful stimulation during intercourse in their pursuit of orgasm.

But then, that’s Brian Morris all over the place. He actively tries to suppress work that doesn’t support his conclusions, he inflates any evidence that suggests circumcision might have a few benefits (there are some!), and dismisses any evidence to the contrary…or worse, twists it around to claim it supports the opposite of the author’s interpretations. All this in defiance of worldwide statements from pediatric organizations that say the evidence for health benefits from circumcision are weak, and that routine circumcision is not recommended.

One other weird thing: why are circumcision advocates so obsessed with this procedure? It’s certainly not that the benefits are as solidly established as they are for vaccination; reading the literature, the most striking observation is the murkiness and insignificance of the evidence. If you’ve got lots of studies, and they vary up and down in their conclusions, and are constantly skirting the margins of likelihood, what’s the best explanation: that there is a strong effect that can only be detected by true believers, or that we’re dealing with no effect at all and people are cherry-picking peaks and troughs from statistical noise? I lean towards the latter. The former is also the excuse used by psychics, UFOlogists, and Bigfoot hunters.

It also doesn’t help that Morris has been affiliated with the Gilgal Society a pro-circumcision organization that also published a book of ‘erotic’ circumcision stories.

Yes, you read that right. Circumcision child porn. Short excerpt below, in rot13.

Ur unq abg ernpurq choregl ohg fbba jbhyq: n srj unvef jrer fgnegvat gb tebj ng gur onfr bs uvf cravf. Arvy jnf gura nfxrq gb yvr ba gur pbhpu sbe gur cravf gb or cubgbtencurq. …gur qbpgbe grfgrq gur svg bs gjb fvmrf bs Tbzpb Pynzc oryy. Qhevat guvf cebprqher Arvy rerpgrq, ohg jnf abg rzoneenffrq ol vg naq znqr ab nggrzcg gb uvqr vg.
Znex pnzr va arkg naq ntnva qebccrq uvf gebhfref ernqvyl. Ur unq ernpurq choregl naq jnf dhvgr jryy qrirybcrq. … Vgf yvxr na ryrcunagf gehax jnf gur qbpgbef pbzzrag, gb juvpu Znex urnegvyl nterrq. … Cubgbtencuf bs uvf cravf jrer gnxra…
Ur unq ernyvfrq nsgre frk rqhpngvba yrffbaf ng fpubby gung ur unq n ceboyrz.
…gur oblf jrer tvira cyragl bs jvar gb erynk gurz. …gur qvfphffvba jnf nobhg gur frk yvirf bs gur oblf naq gurve fpubby sevraqf. Gur qbpgbe nfxrq ubj bsgra gur oblf jnaxrq. … Gur qbpgbe fubjrq gur oblf uvf zvpebfpbcr naq nfxrq vs gurl unq rire frra fcrez haqre bar. … Ur fhttrfgrq gb Znex gung vs ur jnagrq gb, ur pbhyq unir n dhvrg jnax juvyfg Arvy jnf orvat pvephzpvfrq… Guvf jnf rntreyl npprcgrq. … Ur ynl onpx jvgu uvf rlrf pybfrq naq whfg yrg gur qbpgbe trg ba.

Morris has been trying very hard to dissociate himself from Gilgal, at least, but still…eww.

“Gilgal”, by the way, is apparently Hebrew for “hill of foreskins”. Really? They needed a word for that? Double eww.


Frisch M (2012) Author’s Response to: Does sexual function survey in Denmark offer any support for male circumcision having an adverse effect? Int. J. Epidemiol 41 (1): 312-314.

Morris BJ (2007) Why circumcision is a biomedical imperative for the 21st century. Bioessays 29(11):1147-58.

Morris BJ, Bailis SA, Wiswell TE (2014) Circumcision Rates in the United States: Rising or Falling? What Effect Might the New Affirmative Pediatric Policy Statement Have? Mayo Clin Proc doi: 10.1016/j.mayocp.2014.01.001. [Epub ahead of print]

Can we get it as a cosmetic surgery option?

This poor woman in the Netherlands had a bone disorder that caused her skull to continuously thicken, pressing on her brain — so the doctors had a copy of her cranium made out of plastic on a 3-D printer, cut off the top of the skull, and replaced it. It worked, and she’s apparently feeling much better now. So the medical result was awesome.

But awesomer?

skullcap

It was made out of transparent plastic. Now the doctors, of course, covered it up with her scalp and neatly stitched it all together so you can’t even see a scar anymore, but I was thinking, if I had it done, the best thing would be to simply remove all that skin and have my brain pulsing beneath a transparent dome. I’d even pay extra to have some LEDs inserted in patterns in the plastic. Can you imagine how cool it would be to teach neurobiology with your brain hanging out, decorated with little blinking lights?

Maybe someday. A guy can dream.


Here’s a video of the procedure.

Wow, but her skull was really thick. She would have been a master of the Glasgow Kiss, I think.

When your name is prefixed by “reality star”…your ideas are immediately suspect

From the first sentence, I could tell that the opinions of Kristin Cavallari were garbage.

Experts warned against the dangers of following celebrity advice after reality star Kristin Cavallari acknowledged Thursday that she and husband Chicago Bears quarterback Jay Cutler decided not to vaccinate their children.

When directly asked whether she was opposed to vaccines during an appearance on the Fox Business Network program, The Independents, Cavallari said, “we don’t vaccinate.” The reason? “I’ve read too many books about autism and the studies,” she said.

Also, “Chicago Bears quarterback” does not confer any credibility in matters of medicine on Jay Cutler. These are people that should be laughed at.

But then the article cites a doctor:

Homefirst Health Services, meanwhile — if that’s what Cavallari meant — is a Rolling Meadows-based pediatrics practice that embraces home births and shuns vaccines. Dr. Mayer Eisenstein and his practice were the subject of a 2009 Chicago Tribune investigation that shed light on the use of potentially dangerous alternative autism treatments. On the Homefirst website, Eisenstein maintains that “personal religious convictions, not scientific studies, are the main reasons, upon which to base your vaccination decision.”

Is there no accreditation process for medical clinics? How does one that refuses to carry out basic preventive medicine for “religious” reasons, manage to stay in business without the medical establishment — or at least the insurance companies — stomping on them?

The only sensible words in this article…

Alexander said Cavallari’s comments illustrate the problems with celebrity spokespeople, namely that they often have their facts wrong. “Celebrity status does not indicate scientific expertise,” he said.

Good story and a good line

Amy Parker grew up with an all natural lifestyle: avoiding processed food and sugars, an active outdoor lifestyle, eating local organic foods, the whole crunchy natural lifestyle. She was also never vaccinated…and remembers her childhood as a succession of flattening diseases. Now she’s all grown up and is very sensibly vaccinating her own kids and eschewing the woo nonsense, and is happier and healthier than ever. It’s a positive story all around.

Oh, and the good line I’m going to have to steal:

If you think your child’s immune system is strong enough to fight off vaccine-preventable diseases, then it’s strong enough to fight off the tiny amounts of dead or weakened pathogens present in any of the vaccines.

Time for the professional societies to take a stand on Burzynski

The 4th Quadrennial Meeting of the World Federation of Neuro-Oncology is meeting right now in San Francisco, and guess who is presenting there? There are four papers being presented by those criminal frauds of the Burzynski Clinic.

They sure can talk the science talk, can’t they? And they go through all the motions of attending and presenting at meetings of the Society for Neuro-Oncology, which I’m sure looks formidable to the rubes, but when you look at the results of recent reviews of their facilities and protocols (or read the summary in USA Today), they don’t walk the science walk. Read about the patients, or the story of the Burzynski scam. For over thirty years, he has been skating at the edge of credibility by carrying out the rituals of science without going the next step and actually testing his claims, getting rich off desperate people and killing them with bad therapies and sloppy protocols.

I know what these meetings are like. They will be full of professionals in nice dresses and conservative ties, and they will be talking shop and taking notes on the interesting presentations, and I know exactly how they will respond to Burzynskiites: they are beneath them, they will roll their eyes as they skip their talks, and they might grumble a bit at the bar afterwards. And that’s about it. I’ve seen it when creationists get their work into poster sessions at non-peer-reviewed science meetings.

But these guys are worse than creationists. These are con artists giving false hope to dangerously ill patients, using organizations like the SNO as a façade to bilk people out of hundreds of thousands of dollars, and skirting on the proper protocols to give the illusion that they’re doing legitimate science.

It is a huge ethical problem for these societies to provide cover for quacks. I would hope that, at the very least, attendees take time to read the facts about Burzynski and give these con artists a hard time in public; but more significantly, I think the only appropriate thing for the Society for Neuro-Oncology to do is to kick the bastards out. Don’t let them take shelter under your wing any more.

Chilling

That’s all I need, another reason to cower at home in terror of the perils of the real world. Maryn McKenna imagines our Post-Antibiotic Future, that time when bacteria have more thoroughly evolved to resist our medicines — and you’ll be frightened after you read it, too.

Before antibiotics, five women died out of every 1,000 who gave birth. One out of nine people who got a skin infection died, even from something as simple as a scrape or an insect bite. Three out of ten people who contracted pneumonia died from it. Ear infections caused deafness; sore throats were followed by heart failure. In a post-antibiotic era, would you mess around with power tools? Let your kid climb a tree? Have another child?

“Right now, if you want to be a sharp-looking hipster and get a tattoo, you’re not putting your life on the line,” says the CDC’s Bell. “Botox injections, liposuction, those become possibly life-threatening. Even driving to work: We rely on antibiotics to make a major accident something we can get through, as opposed to a death sentence.”

Bell’s prediction is a hypothesis for now—but infections that resist even powerful antibiotics have already entered everyday life. Dozens of college and pro athletes, most recently Lawrence Tynes of the Tampa Bay Buccaneers, have lost playing time or entire seasons to infections with drug-resistant staph, MRSA. Girls who sought permanent-makeup tattoos have lost their eyebrows after getting infections. Last year, three members of a Maryland family — an elderly woman and two adult children — died of resistant pneumonia that took hold after simple cases of flu.

She does offer some slight hope for the future.

What might hold off the apocalypse, for a while, is more antibiotics—but first pharmaceutical companies will have to be lured back into a marketplace they already deemed unrewarding. The need for new compounds could force the federal government to create drug-development incentives: patent extensions, for instance, or changes in the requirements for clinical trials. But whenever drug research revives, achieving a new compound takes at least 10 years from concept to drugstore shelf. There will be no new drug to solve the problem soon—and given the relentlessness of bacterial evolution, none that can solve the problem forever. In the meantime, the medical industry is reviving the old-fashioned solution of rigorous hospital cleaning, and also trying new ideas: building automatic scrutiny of prescriptions into computerized medical records, and developing rapid tests to ensure the drugs aren’t prescribed when they are not needed. The threat of the end of antibiotics might even impel a reconsideration of phages, the individually brewed cocktails of viruses that were a mainstay of Soviet Union medical care during the Cold War. So far, the FDA has allowed them into the U.S. market only as food-safety preparations, not as treatments for infections.

MORE SCIENCE. MUCH MORE.

microRNAs and cancer

I’m trying to raise money for the The Leukemia & Lymphoma Society, and I promised to do a few things if we reached certain goals. I said I’d write a post microRNAs and cancer if you raised $7500. And you did, so I did. I kept my clothes on this time, though, so here’s a more serious picture of yours truly: this is what my students see, which is slightly less terrifying, nicht wahr?

seriously

If you want more, go to my Light the Night fundraising page and throw money at it. If we reach our goal of $10,000, I’ll organize a Google+ Hangout to talk about cancer. Note that we’re also getting matching funds from the Todd Stiefel Foundation, so join in, it’s a good deal.

It’s all epigenetics. Now I’ve gone and done it: I’ve used the “e” word, epigenetics. Nothing seems to fire off well-meaning misconceptions from otherwise sensible pro-science folks than epigenetics — it’s a major new revolution in evolution! It changes everything! It’s a way to get inheritance of acquired characteristics!

Nope.

Epigenetics is routine and has been taken for granted by cell biologists for at least 6 decades. It is simply a principle of gene regulation — switching genes off and on — that persists over multiple cell generations. You aren’t surprised that when liver cells divide, they produce more liver cells, are you? They’ve simply inherited transcription factors and patterns of modification of DNA from their parent cell that restricts their cell fates. There are also patterns of gene expression induced in gametes within parents that modulate initial patterns of gene expression in the fertilized zygote — that is, the state of the parental cells affects the state of the embryo’s cells — which is exactly what you’d expect.

What seems to set people off is that it is an effect of the environment on the state of the genome, and there is this bizarre bias floating around that that can’t happen. Of course it can! Every summer when you get a tan, every winter when you put on another five pounds, every time stress at work makes you prone to get sick…those are environmental factors influencing your biology.

In previous installments of this series, I told you about oncogenes, genes that when over-expressed or over-active switch on cellular processes (like proliferation) that promote cancer, and tumor suppressor genes, which protect against cancer, and which in cancers, are often found to be inactivated or down-regulated. Over-expressed? Down-regulated? That sounds like the sorts of things epigenetic changes can do.

transcription-translation

Further, here’s an interesting observation. Everyone knows the standard pathway: genes in DNA are transcribed into RNA which is then translated into protein. One might naively imagine, then, that the amount of RNA produced would be roughly correlated with the amount of protein produced. It’s not. In analyses of cancers, only 20% of the mRNAs involved showed any correlation between the quantity of mRNA and the quantity of protein — there is something else that is modulating either the amount of translation or the turnover of proteins in the cell, and the fact that 80% of the genes playing a role in cancer show such variation tells us that these kinds of regulatory effects are important.

There must be something stepping in and interfering somewhere between transcription of the gene into messenger RNA, and translation of messenger RNA into protein. One of the somethings is microRNA.

These are tiny little snippets of RNA, typically 22 nucleotides long, that have complementary sequences to their target gene mRNA — they bind to matching RNAs and inhibit translation. Thousands of these microRNAs have been discovered in the last few years, and they’ve also been found to play important roles in regulating gene expression in blood cell lineages, brain activity, insulin secretion, and fat cell development…and in cancer.

As you might guess from the previous articles in this series, there are obvious ways microRNAs could promote cancers. A microRNA that blocks tumor suppressor genes from being expressed could be modified to be produced at a higher level, or a microRNA that would hamper an oncogene’s activity could be mutated to be unable to recognize its target. Easy! Simple! Well, except that this is biology, and nothing is simple in biology (trust me, if you don’t enjoy problems blowing up in your face and getting harder and harder, don’t become a biologist.)

One reason this is complicated is that there are so many details to be worked out — swarms of microRNAs are involved, we don’t know the majority of them, and we don’t know what we’ll learn as we discover more. As Weinberg says,

…the discovery of hundreds of distinct regulatory microRNAs has already led to profound changes in our under- standing of the genetic control mechanisms that operate in health and disease. By now dozens of microRNAs have been implicated in various tumor phenotypes, and yet these only scratch the surface of the real complexity, as the functions of hundreds of microRNAs known to be present in our cells and altered in expression in different forms of cancer remain total mysteries. Here again, we are unclear as to whether future progress will cause fundamental shifts in our understanding of the pathogenetic mechanisms of cancer or only add detail to the elaborate regulatory circuits that have already been mapped out.

But also, we’ve learned that it’s not simply a matter of a few short bits of RNA getting transcribed and dumped into the cytoplasm — there is a whole elaborate cellular apparatus dedicated to microRNA processing. Behold!

oncomirs

Don’t panic, I’ll hold your hand and we’ll walk through it. miRNA genes are first transcribed into RNA by RNA polymerase II; notice that the transcript, which is called a pri-miRNA (or primary microRNA) contains some long stretches of internal complementarity, and that the RNA folds into a hairpin loop. This RNA is grabbed by an RNA binding protein, Pasha, and an RNA cutting enzyme, Drosha, which snips off some excess bits to produce a smaller stem-loop structure about 70 nucleotides long, which is partially double stranded RNA. It also gets a new name: Pre-miRNA. Pre-miRNA is then exported out of the nucleus and into the cytoplasm by a channel protein, Exportin-5.

Once in the cytoplasm, another RNA cutting enzyme, aptly named Dicer, snips off a few more bits to reduce it to two very roughly complementary RNA strands, now called the miRNA:miRNA* duplex. One of these strands is then loaded into a set of proteins to form the miRNA-associated multiprotein RNA-induced silencing complex, thankfully called miRISC for short.

The short, 22-nucleotide long strand of RNA in the miRISC is what gives it specificity — the miRISC proteins carry it along as a template to match against messenger RNAs they encounter. If the miRNA makes a perfect match to some unfortunate strand of messenger RNA, the miRISC cuts up the mRNA to destroy it. If it’s an imperfect match over just some significant fraction of the 22-nucleotide sequence, it it just locks up the RNA and represses its translation.

The way these can affect cancer is illustrated below. If a microRNA that inhibits an oncogene is mutated (b), that oncogene will increase the amount of protein produced from the available RNA; the oncogene could even be normal in sequence and function, and just the boost in its signal could contribute to tumorigenesis. Alternatively, a mutation in a microRNA gene that affects a tumor suppressor could amplify its production (c), producing a greater inhibition of a healthy gene that acts to prevent tumorigenesis.

MicroRNAs can function as tumour suppressors and oncogenes. a | In normal tissues, proper microRNA (miRNA) transcription, processing and binding to complementary sequences on the target mRNA results in the repression of target-gene expression through a block in protein translation or altered mRNA stability (not shown). The overall result is normal rates of cellular growth, proliferation, differentiation and cell death. b | The reduction or deletion of a miRNA that functions as a tumour suppressor leads to tumour formation. A reduction in or elimination of mature miRNA levels can occur because of defects at any stage of miRNA biogenesis (indicated by question marks) and ultimately leads to the inappropriate expression of the miRNA-target oncoprotein (purple squares). The overall outcome might involve increased proliferation, invasiveness or angiogenesis, decreased levels of apoptosis, or undifferentiated or de-differentiated tissue, ultimately leading to tumour formation. c | The amplification or overexpression of a miRNA that has an oncogenic role would also result in tumour formation. In this situation, increased amounts of a miRNA, which might be produced at inappropriate times or in the wrong tissues, would eliminate the expression of a miRNA-target tumour-suppressor gene (pink) and lead to cancer progression. Increased levels of mature miRNA might occur because of amplification of the miRNA gene, a constitutively active promoter, increased efficiency in miRNA processing or increased stability of the miRNA (indicated by question marks). ORF, open reading frame.


MicroRNAs can function as tumour suppressors and oncogenes. a | In normal tissues, proper microRNA (miRNA) transcription, processing and binding to complementary sequences on the target mRNA results in the repression of target-gene expression through a block in protein translation or altered mRNA stability (not shown). The overall result is normal rates of cellular growth, proliferation, differentiation and cell death. b | The reduction or deletion of a miRNA that functions as a tumour suppressor leads to tumour formation. A reduction in or elimination of mature miRNA levels can occur because of defects at any stage of miRNA biogenesis (indicated by question marks) and ultimately leads to the inappropriate expression of the miRNA-target oncoprotein (purple squares). The overall outcome might involve increased proliferation, invasiveness or angiogenesis, decreased levels of apoptosis, or undifferentiated or de-differentiated tissue, ultimately leading to tumour formation. c | The amplification or overexpression of a miRNA that has an oncogenic role would also result in tumour formation. In this situation, increased amounts of a miRNA, which might be produced at inappropriate times or in the wrong tissues, would eliminate the expression of a miRNA-target tumour-suppressor gene (pink) and lead to cancer progression. Increased levels of mature miRNA might occur because of amplification of the miRNA gene, a constitutively active promoter, increased efficiency in miRNA processing or increased stability of the miRNA (indicated by question marks). ORF, open reading frame.

This is not simply a hypothetical possibility, either. Dozens of miRNA genes have been implicated in human cancers — they show abnormal variations in expression in specific cancers and also have known oncogene/tumor suppressor targets.

miCancer

These microRNAs are a relatively new scientific phenomenon — they weren’t even a blip on the radar when I was a graduate student, and when I did start hearing about them in the 1990s, they were thought of as a weird mechanism found in highly derived nematodes. Now we’re seeing them everywhere, and beginning to recognize their importance in controlling all kinds of genes. The process of developing tools to control miRNAs is underway in the laboratory, but it has a long way to go before we have effective clinical tools to combat cancer with miRNAs or antagonists to miRNAs. At the very least, it’ll be another tool we can use.


Calin GA, Croce CM (2006) MicroRNA-cancer connection: the beginning of a new tale. Cancer Res. 66(15):7390-4.

Esquela-Kerscher A, Slack FJ (2006) Oncomirs – microRNAs with a role in cancer. Nat Rev Cancer 6(4):259-69.

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

“it is time for the genitals of all children to be protected from people with knives and strong religious or cultural beliefs”

Taslima has the news: experts in Sweden, Norway, Finland, Denmark, and Iceland are proposing a complete ban on circumcisions of all types. Unfortunately, it’s a little premature to say it will happen: what we have right now is a group of ombudsmen for children, paediatricians, and paediatric surgeons passing a resolution at a meeting. There is no law yet.

But it certainly makes sense. Hacking up babies’ crotches is perverse and bizarre and unnecessary.

What are tumor suppressor genes?

I’m trying to raise money for the The Leukemia & Lymphoma Society, and I promised to do a few things if we reached certain goals. I said I’d write a post explaining what tumor suppressor genes are, while wearing a pirate hat and nothing else, if we raised $5000. Shiver me timbers, I did! And it’s cold!

madnakedpirate

If you want more, go to my Light the Night fundraising page and throw money at it. I’ll write about microRNAs and cancer when we hit $7500. Note that we’re also getting matching funds from the Todd Stiefel Foundation, so join in, it’s a good deal.

There’s a basic principle in biological homeostasis (and it’s also true in cybernetics) that for every process that turns something on, you have an anti-process that turns it off. When you look at what’s going on inside the cell, you’ll often get the impression that it’s spinning its wheels — every protein, for instance, is being degraded at about the same rate that it’s being synthesized. The whole cell is in a state of dynamic equilibrium, in which it might look like the concentration of some protein is constant overall, but when you look closely, individual protein molecules are being constantly made, instantly targeted for destruction, and dismantled…only to be nearly instantly replaced by a duplicate. Everything is in a state of flux, and it looks terribly wasteful, but it means that everything is fluid and flexible and the cell is incredibly responsive to subtle cues.

Last time I wrote about oncogenes, genes that are activators of crucial cellular processes like cell division, and I told you that these play a role in cancer by sending faulty signals that switch on uncontrolled cell division. Given the above principle, you might expect that if there are gene products that turn on cell division, there ought to also be gene products that turn off cell division, a kind of anti-oncogene. And there are! They’re called tumor suppressor genes.

While acting in opposition to oncogenes, tumor suppressor genes typically exhibit another difference in behavior that sets them apart. Cancer causing mutations in oncogenes are usually dominant: that is, the mutation doesn’t just knock out the gene, it has to make a hyperactive gene, and just one mutant copy gone rogue is enough to start switching on cellular activity. Tumor suppressor gene mutations tend to be recessive.

You’ve usually got two copies of every gene. A tumor suppressor works to shut down renegade activity, and a cancer-causing mutation in one is most often simply going to be a mutation that destroys the gene — but since you’ve got two copies, it has a backup. Cancer needs to kill both copies of the tumor suppressor to escape from its anti-tumor actions.

The best known tumor suppressor gene is BRCA1, and it exhibits this behavior. BRCA1 is a good gene — it’s working to protect you from breast cancer. For most of us, every cell in our body has two functional copies of BRCA1. It’s like having two cops patrolling the beat, prepared to fight off any cancer threat, and for cancer to succeed, it has to kill off both. Even one left functional can suppress any effort by the cell to go hyperactive and proliferate. A mutation that knocks out one copy is rare, but two mutations that knock out both are even more rare — it follows two-hit kinetics, which means you multiply the probability of the two events together.

You will occasionally hear about someone being at high risk of cancer because they carry a bad allele of BRCA1 — Angeline Jolie was in the news about this recently. What has happened here is that the person was born inheriting one broken copy of the BRCA1 gene — their cells only have one cop on the beat. They aren’t born with cancer — that one copy of BRCA1 is sufficient to keep them safe — but now they are at much higher risk of an accidental mutation taking out their sole protector than if they had two.

Another well known tumor suppressor gene is Rb, the gene that when mutant can lead to retinoblastoma, or cancers of the eye. It also exhibits two hit kinetics, in that familial retinoblastoma is caused by inheritance of one mutant Rb allele, so that all it takes is one mutation later in life to lead to cancer. Sporadic retinoblastoma, that is retinoblastoma without previous examples in the family, is much rarer, because it requires a first somatic mutation and a second mutation later to take out the second copy.

famRb

Having an enabling mutation in one copy at birth so greatly increases the chance of retinoblastoma that afflicted individuals are likely to have bilateral cancers affecting both eyes, while it’s so rare in sporadic cases that it is almost always unilateral, affecting only one eye.

OK, you understand the principle. Last time, I wrote about the oncogene Ras, which, to make it simple switches on the mitotic machinery and promotes cell division. Does it have an anti-gene product that opposes Ras and switches off cell division?

Of course there is. Several actually. One example: recall that I told you that Ras is activated by binding GTP, and deactivated by converting GTP to GDP, and that Ras itself has GTPase activity and therefore works to switch itself off. There are also tumor suppressor proteins that are called GAPs, or GTPase activating proteins, that enhance Ras’s GTPase activity. One of them, called NF1 or Neurofibromin, binds to Ras and elevates its potency as a GTPase approximately 1000-fold — it basically makes Ras ultra-good at shutting down and doing nothing.

nf1gap

Oncogenes and tumor suppressors are the yin and yang of cellular regulation. Cancer cells often contain hyperactive oncogenes, and have shut down tumor suppressors…which suggests that one strategy for treating cancer is to develop inhibitors of oncogenes, and to repair, replace, or elevate expression of tumor suppressors. And that’s a rather pat explanation of some viable general strategies that of course encounter all kinds of additional complexities.


Donovan S, Shannon KM, Bollag G (2002) GTPase activating proteins: critical regulators of intracellular signaling.. Biochim Biophys Acta 1602(1):23-45.

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

Weinberg, RA (2014) Biology of Cancer. Garland Science, New York.