percolation communications


1 Comment

A Strange Cancer in Animals That Broadens Our Understanding of Cancer Biology

by Anna Lau, PhD, Medical Writer

We generally think about cancer as a disease of individuals, but doing so could limit our view of cancer biology and prevents us from appreciating the complexity of this disease. Cancer can also be a disease of families. There are numerous heritable genetic mutations that greatly predispose families to the development of certain cancers (see here, here, and here).

What if cancer were a disease of a species, a contagious disease that could be passed from person to person through contact? Thankfully, human cancer is not usually contagious—but such cancer is not unheard of. There have been cases of direct transmission of cancer between people (passed between individuals through physical contact): from mother to fetus, from fetus to fetus between twins, and from organ or stem cell donor to recipient via the donated tissue. Let it be clearly emphasized that these are rare events. Thus far, no human cancer has developed the capacity to be easily transmitted through direct contact.

There are certain cancers that can be spread from person to person through an infectious agent, like a virus. The human papillomavirus can be transmitted through sexual contact and cause many kinds of cancers in both men and women. But this does not mean that the cancer itself is the contagion, only the virus.

But there are examples in the animal kingdom of contagious cancers that are directly transmissible. One is extraordinarily old, the other quite new, and appreciating their differences and similarities to human cancers can broaden our total understanding of cancer biology.

Devils die, but dogs defy a dreaded disease.

Around 1996, researchers discovered a cancer decimating the Tasmanian devil population. The cancer, termed Tasmanian devil facial tumor disease (DFTD), arose from a single clonal cell lineage in a single devil, but the cancer has spread like wildfire. Symptoms start as lesions on the face, neck, and mouth of affected animals, then enlarge (>3 cm diameter) and ulcerate. Death ensues within months of initial appearance of lesions. Since the emergence of DFTD, the devil population has been devastated, putting the animals at risk of local extinction within just a few decades! Transmission of DFTD occurs through direct contact between animals, during which tumors are transmitted as allografts that are genetically distinct from their hosts. In other words, the cancer is physically passed from one devil to another through normal contact, the cancers examined from different devils are genetically identical (ie, clonal), and the cancers are able to thrive—that is, they do not provoke a host immune response.

Figure 1. Tasmanian devil with facial tumor disease. Photo by: Menna Jones (creativecommons.org/licenses/by/2.5), via Wikimedia Commons.

Tasmanian devil with facial tumor disease. Photo by: Menna Jones (creativecommons.org/licenses/by/2.5), via Wikimedia Commons.

There is another clonally transmissible cancer that affects dogs, called canine transmissible venereal tumor (CTVT). CTVT is highly prevalent among dogs living in tropical and subtropical urban environments. Genome sequencing studies have confirmed the clonality of two CTVT tumors from dogs on distant continents and showed this cancer to be the oldest known somatic cell lineage. According to this research, CTVT arose in an ancient wolf or dog about 11,000 years ago and has been passed from dog to dog as allografts ever since then. (One can only imagine what a long, strange trip that has been.) Unlike DFTD, however, CTVT is rarely fatal. Once transferred to a new host, CTVT undergoes an initial progressive phase, marked by rapid tumor growth generally lasting for weeks, then enters a stable phase of slower tumor growth lasting from weeks to indefinitely, and finally settles into a regression phase in most dogs, during which tumors shrink and disappear. In other words, the canine immune system can overcome CTVT.

Figure 2. Dog genitals with transmissible venereal tumor.  Spugnini EP, et al. J Exp Clin Cancer Res. 2008;27:58.

Dog genitals with transmissible venereal tumor. Spugnini EP, et al. J Exp Clin Cancer Res. 2008;27:58.

DFTD and CTVT are strange, but they share properties with human cancers.

For DFTD and CTVT to propagate, they must (a) have a route of transmission, (b) survive and thrive in a new environment, and (c) evade the host immune system in the new location (at least for a period). Notably, these are requirements that human cancer cells also must meet to metastasize. Recent studies show how DFTD evades the host immune system with a strategy something like getting past a doorman. DFTD suppresses antigen presentation—it doesn’t announce itself or sign in at the “front desk”—so the “doorman” doesn’t know that DFTD has entered. CTVT does something similar, except that it suppresses antigen presentation only at first, during the progressive phase; during the stabilization and regression phases, antigen presentation is largely restored.

Suppression of antigen presentation is a tactic that human cancer cells use to evade detection when they metastasize from a primary to a secondary tumor site. What we know about CTVT suggests that restoring antigen presentation could reestablish disease control. At present, a number of agents that can bolster antigen presentation are under investigation for the treatment of human cancer. Such an immunotherapeutic approach could work, but the jury is still out.

It has also been shown that telomere length in DFTD cells is regulated. In simple terms, telomeres are to chromosomes what aglets (the protective tips) are to shoelaces; telomeres protect chromosome ends from damage, such as degradation or aberrant fusions with other chromosomes. Telomere length correlates with replication potential: the longer the telomeres, the more times a cell can divide. Telomeres in DFTD cells aren’t longer than those in normal Tasmanian devil cells, but they can be elongated when they get too short. (Imagine replacing an aglet when it starts to wear out.) Furthermore, telomere length in DFTD cells appears to be stabilized by a protective protein complex. (Imagine also wrapping an aglet in duct tape after replacement.) In human cancers, aberrant telomere homeostasis is a common feature. Efforts are underway to target telomerase, the enzyme responsible for lengthening short telomeres, as one approach to fight cancer.

What are the implications of unusual animal cancers for human cancer biology?

The existence of clonally transmissible cancers means that cancer can be a disease of a species. One could argue that such a cancer arose in Tasmanian devils because they are highly inbred and genetically similar. But such a cancer also arose in and spread successfully among genetically diverse canine breeds, suggesting that susceptibility of a species to this type of cancer is not restricted to those that are inbred. At present, it’s not known how DFTD or CTVT originally arose, or what specific mutations conferred their capacity to thrive in this unusual way, so it’d be pure speculation whether this could happen in another animal species, including humans. But considering that the clonally transmissible cancers and human cancers share common escape and survival mechanisms, we speculate that it is possible, although highly unlikely (since this has only arisen twice so far in the known history of human and animal disease studies). We don’t fully understand yet how most dogs are able to keep this cancer in check, but that they do is evidence of the strength and plasticity of the immune system. By investigating the origins of these cancers, observing their evolution, and understanding their interactions with their respective hosts, we can gain a broader view of cancer biology and how we can fight it better in humans.

The capacity of clonal cancer cells to be passed through a species attests to the awesome power of natural selection, which has led these cancers to evolve to be fit enough to survive for millennia. Sure, there are any number of organisms that have been around for at least that long, but the clonal cancers survive without sexual reproduction, an important mechanism used by many species to mix genes in new combinations. In some ways, we can liken these clonal cancers to an asexually reproducing organism, in which offspring are clones of the parent.

The future of the devils hangs in the balance.

From an evolutionary standpoint, it doesn’t benefit the DFTD cancer to kill off its host too quickly or completely, because then it too would perish. Extrapolating from the CTVT experience, it’s conceivable that DFTD and the devil could co-evolve to balance tumor growth with suppression by the host immune system. Given enough time, this could happen… but the Tasmanian devils’ advocates aren’t waiting for nature to run its course; they’re already working on a vaccine. Let’s hope investigators make it in time to save the devils.

Here’s how you can help.


Leave a comment

Cat Lady Not So Crazy After All: Cancer Breakthrough…in the Litter Box?!

By Alison Wagner, PhD, Medical Writer

kitten in litter box

To be clear, it is not the actual waste of the cat that is so intriguing (although my dog would beg to differ). It is Toxoplasma gondii (T. gondii), a parasite that requires a cat host during its lifecycle and is expelled in the feces, that has scientists from different fields, including behavioral neuroscience, immunology, and oncology, interested.

T. gondii must begin and complete its lifecycle in cats, but any warm-blooded animal can serve as an intermediate host. In these instances, the animal typically consumes the oocyst form of T. gondii. Once consumed, the oocyst ruptures and there is a brief period of fast replication and invasion of tissues (tachyzoite stage). The host’s immune response then triggers T. gondii to transform into the less active bradyzoite or chronic infection stage.
life cycle

Lifecycle of Toxoplasma gondii. (LadyofHats, Wikimedia Commons)

T. gondii is best known for giving pregnant women a great excuse to hand over litter box duties to someone else, and for good reason: first-time maternal infection with T. gondii during pregnancy can have significant effects on the developing fetus or even cause miscarriage. These effects are at least partially due to an inflammatory reaction of the maternal immune system to the parasite. People with immune deficiencies, such as HIV patients, are also at risk for complications associated with T. gondii infection, but the widespread belief until recently was that infection with T. gondii in healthy adults, though common (currently up to a third of the global population), was generally asymptomatic.

However, researchers noted that mice infected with T. gondii showed a peculiar behavior – they lost their fear response to cats (specifically, to cat odors). Causing that change in behavior is advantageous to T. gondii because the lack of fear would improve the odds that a cat could kill and eat the mouse, which in turn would perpetuate the parasite’s lifecycle. Interestingly, this effect lasted long after T. gondii had been cleared from the body, indicating that it is not a direct effect of the parasite itself. The authors of the study suggest that the immune system response that continues after the parasite is eliminated might be the culprit, rather than the actual parasite, which would explain why the behavior persists.

If T. gondii can make mice behave contrary to their natural instincts, what about humans? As it turns out, infection with T. gondii does appear to alter human behavior. For instance, infected men are said to be on average more jealous and more likely to disregard rules, while infected women are typically more warm and outgoing. T. gondii infection is also linked to an increased risk of schizophrenia, possibly due to an inflammatory response that increases release of dopamine, the key neurotransmitter known to be involved in schizophrenia.

Many media outlets immediately linked these changes to “crazy cat lady syndrome” (see here, here, here, and here). However, in my humble opinion, the behavioral changes don’t fit the stereotypical crazy cat lady. The characteristics I associate with CCLs include “introverted,” “unsocial,” and “misanthropic,” not “warm and outgoing.”

As fascinating as the effects of T. gondii on behavior are, what does that have to do with cancer and a potential new therapy? As Heather Lasseter discussed in her cancer immunotherapy post, many of the most promising cancer vaccines in development now address the problem of inhibition of normal T-cell response by molecules like CTLA-4 and PD-1 that are released by the cancer cells. And as I discussed in my last post (“Why Wolverine Will Never Get Cancer”), the immune system is intimately involved in whether cancer cells survive and thrive or not. Figuring out how to manipulate the immune system accordingly would be an enormous breakthrough in cancer therapy.

It turns out that T. gondii elicits a very specific reaction from the immune system. Rather than trying to “hide,”  T. gondii activates T cells and other inflammatory responders such as natural killer (NK) cells. This provokes the immune system to do exactly what it is supposed to do – attack invaders – and  limits the growth of T. gondii into surrounding tissue. It may seem like the worst war strategy ever for T. gondii to basically wave a flag at the enemy while shouting taunts. However, this strategy works because of the parasite’s specific lifecycle (see above) – the immune response to the invader actually aids in its transformation into bradyzoites, an essential part of that lifecycle.

Because T. gondii is so excellent at producing T-cell and NK-cell response, it can induce the exact conditions needed to stimulate the immune system and overcome the inhibitory signals from cancer cells. Indeed, researchers using a non-replicating* form of T. gondii as a basis for a cancer vaccine found that mice given this vaccine were able to achieve extraordinarily high levels of survival against extremely aggressive cancers. Immune cells in the tumor microenvironment showed higher levels of activation, indicating that the T. gondii–based vaccine had jump-started the immune system into attacking the tumor cells more aggressively and causing tumor regression. These kinds of studies have not yet been conducted in human patients – the science is still very much in the preclinical phase – but given that mice and humans are both intermediate hosts to T. gondii and show similar immune responses to the parasite, it is reasonable to anticipate positive results as this potential vaccine is tried in humans.

*The non-replicating part is key here – giving people a systemic parasitic infection is generally not considered good practice, especially when those patients are potentially immunocompromised. The vaccine that is in preclinical development is based on T. gondii, but does not produce a live infection, because a key gene for replication of T. gondii is removed.

So what does this all mean? Some might say: eat cat poop to prevent cancer. I would suggest holding off on that. It’s likely that the T. gondii (or T. gondii–like vaccine) would need to be present directly at the tumor site rather than distributed systemically; also, most indoor house cats don’t actually have T. gondii (sorry, pregnant ladies hoping to get out of litter box duty). You would then have eaten cat poop for no good reason, and that’s just disgusting. However, we can conclude that while we are making progress on understanding the immune system and how it can be a major player in cancer therapeutics, there may just be a few shortcuts we can take, provided by nature (and cat poop).


Leave a comment

Curbing the Opioid Epidemic: A New Weapon Against Heath Ledger’s Killer

by Heather Lasseter, PhD, Medical Writer

The high-profile deaths of actors Heath Ledger and Philip Seymour Hoffman have brought the stark reality of prescription and illegal drug abuse into the public eye. The loss of Heath Ledger – who died from a fatal overdose of oxycodone, hydrocodone, and benzodiazepines – highlights the “opioid epidemic” that has been sweeping the United States. But the good news? Expanded availability and new formulations of drugs designed to combat drug overdose may help curb the growing number of opioid overdoses.

According to the Centers for Disease Control and Prevention (results published in the Journal of the American Medical Association), deaths from drug overdoses have increased steadily over the past two decades, with opioid drug use contributing heavily to these fatalities.

Data from the Centers for Disease Control and Prevention (www.cdc.gov).

Data from the Centers for Disease Control and Prevention (www.cdc.gov).

And the statistics surrounding drug overdose are staggering:

  • 38,329 people died of drug overdose in 2010 – a more than 2-fold increase from 1999
  • More than 100 people die from drug overdose every day in the US
  • Drug overdose was the leading cause of death due to injury, surpassing motor vehicle accidents as a cause of death among 25- to 64-year-olds

Shockingly, the majority of overdose deaths in recent years involve pharmaceutical drugs. Of these, opioid analgesics like oxycodone, hydrocodone, and methadone played a prominent role: pharmaceutical opioids were involved in 74% of fatal drug overdoses, and they contributed to more fatalities in 2008 than the street drugs cocaine and heroin combined.* Aside from the tragic loss of life, the monetary costs of opioid abuse – including workplace, healthcare, and criminal justice costs – were more than $55 billion in 2007.

*According to the 2012 National Survey on Drug Use and Health, over 2,000,000 individuals aged 12 and older were dependent on or had abused pain killers in the past year, compared to approximately 1,120,000 and 470,000 individuals who had used cocaine or heroin, respectively.

Data from Jones CM, et al. JAMA. 2013;309(7):657-659. *Deaths are not mutually exclusive; deaths involving more than one drug or drug class are counted multiple times.

With sales of these pharmaceutical painkillers skyrocketing by 300% since 1999, a solution is clearly needed to turn the tide in opioid use that contributes to overdose deaths.  

A medication that specifically combats opioid overdose exists, and has been used for years in medical settings. This drug, naloxone,* can reverse the fatal effects of opioids and, as part of emergency response kits distributed to heroin users and other opioid drug users, has been shown to reduce fatal overdoses.

*Naloxone should not be confused with naltrexone, which is longer acting and used to treat alcohol and opioid dependence rather than acute drug overdose. 

So how does naloxone combat opioid overdoses?

Opioid agonists, like oxycodone or heroin, bind to opioid receptors located throughout the central and peripheral nervous systems as well as in the gastrointestinal tract. While their action leads to clinically beneficial effects such as analgesia, they can also produce feelings of euphoria (hence the abuse potential) and dangerous side effects including respiratory depression, decreased heart rate, loss of consciousness, and even coma. Naloxone works by rapidly reversing the underlying cause – not just the symptoms – of an opioid overdose. With an extremely high affinity for μ-opioid receptors, and as a competitive antagonist at these receptors, naloxone essentially floods the nervous system and knocks opioids out of the way.  This results in a rapid reversal of overdose symptoms – giving the opioid user a “second chance.”

Crystal structure of the μ-opioid receptor bound to a morphinan antagonist, from WikimediaCommons by Metilisopropilisergamida.

Crystal structure of the μ-opioid receptor bound to a morphinan antagonist, from WikimediaCommons by Metilisopropilisergamida.

Because naloxone undergoes high first-pass metabolism, oral ingestion of naloxone only affects receptors in the gastrointestinal tract. Hence, it must be delivered by intravenous, subcutaneous, or intramuscular injections, or via the nasal passages. However, first responders such as police officers have expressed reluctance to administer naloxone injections to overdose victims and are similarly hesitant to use naloxone nasal inhalants due to their off-label use. The availability of these medications has also been limited, especially in rural areas.

Enter the new prescription treatment Evzio™.

Evzio,a naloxone HCl injection, was fast-tracked to receive approval by the US Food and Drug Administration on April 3, 2014 – 2 months ahead of the planned approval date – and became available on July 10. So where does Evzio fit in? Unlike other naloxone treatments such as Narcan® (which can be used either as an injectable or inhalable agent), Evzio is the first FDA-approved naloxone injector that permits easy administration without training, similar to the EpiPen® used for treatment of anaphylaxis. Evzio rapidly delivers a single 0.4 mg dose of naloxone via a handheld auto-injector that administers either an intramuscular or subcutaneous injection. The device also provides visual and voice instructions for how to deliver the medication, and can be easily transported or stored. This puts the power to combat overdose firmly in the hands of friends and family – those most likely to be at the scene of an overdose.

Nevertheless, “rescue” treatments for drug overdose face steep criticisms – and potential barriers to implementation.  

Detractors suggest that easy access to overdose treatments will provide opioid users with a false sense of security and encourage risky and/or illegal drug use, despite evidence that enrollment in naloxone and resuscitation programs produces a decline in drug use – at least among heroin users. Further, high costs associated with new treatments like Evzio may create a significant barrier to use. Speaking to the Boston Globe, drug policy researcher Leo Beletsky of Northeastern University estimated that Evzio may cost $200 per dose compared to $15-$40 for the nasal spray. (Kaléo, the manufacturer of Evzio, is offering a Patient Assistance and Payment program to enable more widespread access to the drug.)

Another salient point is that drugs like Evzio and Narcan do not preclude prompt emergency medical attention when an overdose is suspected. These medications only combat opioid overdose, not overdose of other medications like benzodiazepines, and their effects may not outlast those of the opioids, whose half-lives (typically multiple hours) are longer than that of naloxone (30-80 minutes). Thus, an individual may still be at risk of dying after receiving initial treatment, necessitating repeated dosing and additional medical care.

That said, drug overdose prevention programs are a powerful force for combating the rising tide of opioid-induced deaths. For instance, Project Lazarus, North Carolina’s Wilkes County overdose prevention program, has been advocating the use of naloxone to reverse opioid toxicity and has developed other educational tools for emergency department and primary care physicians. The result? The county, which had the third highest rate of drug overdoses in the nation, has seen a progressive, 28-month drop in overdose deaths for a 69% reduction in just over 2 years. Officials hope this program may be spread across the state and serve as a model for programs nationwide.

It is possible to deliver pain relief without a heavy overdose risk – and opioids remain a powerful part of our arsenal for treating acute and chronic pain such that removing access would be unethical for those in genuine need. But as stated by the FDA, “opioids are powerful medications that can help manage pain when prescribed for the right condition and when used properly. But when prescribed by physicians to patients who should not receive them, or when used improperly or for recreational purposes, they can cause serious harm, including overdose and death.”

For more information on deaths related to pharmaceutical drug and opioid overdose, please visit the CDC webpages:
www.cdc.gov/homeandrecreationalsafety/overdose/facts.html
www.cdc.gov/media/releases/2013/p0220_drug_overdose_deaths.html


Leave a comment

How Gene Therapy Is Like a Weeble

By Anna Lau, PhD, Medical Writer

My Weebles collection. Don’t judge. WEEBLES is a registered trademark of Hasbro, Inc.

My Weebles collection. (Don’t judge.)

In 1963, at the dawn of the molecular biology age, Dr. Joshua Lederberg anticipated “the interchange of chromosomes and segments,” predicting that “the ultimate application of molecular biology would be the direct control of nucleotide sequences in human chromosomes, coupled with recognition, selection and integration of the desired genes…” His idea describes the basic principle of gene therapy. Less than three decades later, in 1990, the first report was published of successful retrovirus-mediated gene transfer in people. This raised hopes that genetic disorders would one day be cured by introducing functional genes into patients. But what ensued was a series of promising steps forward followed by steps back.

Jesse Gelsinger was a young man who suffered from ornithine transcarbamylase deficiency, an X-linked disorder that affects protein metabolism. In 1999, Jesse was enrolled in a pilot study to assess the safety of gene therapy in children with genetic diseases. He received a dose of adenoviral vector containing a working copy of the defective gene that caused his disease. Jesse developed a systemic inflammatory response that none of the first 17 patients in the pilot study had. He died several days later.

Like a Weeble, gene therapy wobbled, but it didn’t fall down. Researchers never gave up refining technologies.

The tragic death in 1999 of a young man from an acute innate immune response to an adenoviral vector spurred researchers to explore safer, less immunogenic vectors, like adeno-associated viral (AAV) and lentiviral vectors. The newer vectors are also preferable over retroviral vectors, which can integrate willy-nilly into the host genome, and cause insertional mutagenesis leading to cancer.

Schematic of the CRISPR/cas system. Cas9 (light blue blob) is a bacterial DNA endonuclease. Guide RNA (blue strand) contains a sequence that matches the target DNA sequence to be cut, which is marked by an adjacent recognition sequence called a PAM motif (orange strands). Cas9 generates site-specific double-stranded DNA breaks that need repair. If donor DNA (purple strands with black homology regions) is provided during repair, then homology-directed repair can occur, and new DNA can be introduced at the break site.

Non-viral approaches are also under investigation that would circumvent issues related to viral vectors, including a transposon-based system and an exciting new system called CRISPR/cas. CRISPR/cas serves as an adaptive immune system in bacteria, but has been exploited by researchers to make precise changes to DNA sequences in an array of model organisms (plants, yeast, nematodes, zebrafish, and mice) and in human cells. More importantly, researchers have used CRISPR/cas to successfully correct genetic defects in mouse models of human diseases, tyrosinemia and congenital cataracts.

Other endonuclease-based methods of site-directed mutagenesis, namely ZFN (zinc finger nucleases) and TALEN (transcription activator-like effector nuclease), have been developed. These are not discussed here, however, because the customization needed to target ZFNs or TALENs to specific sites in the genome is considerably more cumbersome, compared with CRISPR/cas. Because ZFN is an older technology, it has been used safely to disable the major coreceptor, CCR5, for HIV entry into host T cells in HIV-positive patients.

Researchers are also targeting more “gene therapy-amenable” disorders…

Some disorders are more amenable than others to the gene therapy approach, depending on the tissue type affected, the amount of therapeutic protein needed, and “invisibility” to the immune system, among other factors. For instance, the CFTR gene defect that causes cystic fibrosis must be corrected specifically in the lungs to affect the lung phenotype of the disease, whereas the factor IX (F9) gene defect that causes hemophilia B need not be corrected in a particular tissue as long as therapeutic levels of coagulation factor are present in plasma.

How much function does a corrective gene need to restore to be clinically meaningful? That can vary by disorder. For instance, expression of factor IX at >5% of normal levels represents a mild form of hemophilia B, so striving to reach this expression level is a reasonable target. (This study strove for >3% of normal levels.) But it’s not known exactly how much functional CFTR protein would be needed to rescue a patient with cystic fibrosis (although one group suggests at least 25%).

…and more “gene therapy-amenable” organs.

The eye is an organ particularly suitable for gene therapy because it is small, accessible, and sequestered from the immune system. This so-called immune privilege means that local immune and inflammatory responses are limited. There are about a dozen ongoing clinical studies of gene therapy for genetic eye disorders (some of which are described here).

Still, most gene therapy clinical studies are in cancer.

Cancer is the second leading cause of death in the US, so there is tremendous interest in applying knowledge of cancer molecular biology and genetics to finding its cure. As of June 2012, 1843 gene therapy clinical studies worldwide had been completed, were ongoing, or were approved to start. Of these, 1186 (64%) were studies in cancer. Gene therapy has been used with a wide variety of cancers in adults and in children, including gastrointestinal, gynecologic, lung, neurologic, skin, and urologic solid tumors and hematologic malignancies. The strategies used against cancer have included insertion of tumor suppressor genes, immunotherapy, oncolytic virotherapy, and gene-directed enzyme prodrug therapy.

Distribution of topics in gene therapy clinical studies, as of June 2012.

Investors are catching on to gene therapy. Will everyone else follow suit?

Since the beginning of 2013, biotechnology and pharmaceutical firms exploring gene therapy approaches have raised hundreds of millions of dollars in capital to fund their research. Now, not only must researchers overcome biological barriers to successful gene therapy (achieving sufficient gene transfer in target tissue, sustaining expression over time, limiting immune response to the gene delivery system, etc). Companies will also need to figure out how to scale up gene therapy approaches, price these approaches appropriately, and convince doctors, patients, and insurance carriers that gene therapy is a safe, efficacious, cost-effective approach to treatment.

In 2010, a new generation of Weebles was introduced, marking their comeback nearly 40 years after the originals. Dr. Lederberg’s prediction for gene therapy will take longer than that to be fulfilled—perhaps by 2023, six decades after his original prediction? Fingers crossed.

WEEBLES is a registered trademark of Hasbro, Inc.


Leave a comment

Why Wolverine Will Never Get Cancer

by Alison Wagner, PhD, Medical Writer

Wolverine?

Not this one. (WikiCommons)
Not this one. (photo from the National Park Service, accessed from WikiCommons)
This one! (Alison Wagner)
This one!
(photo by Alison Wagner)

 

 

 

 

 

 

 

 

 

An episode of the TV series The Big Bang Theory featured its lovable group of “nerds” debating who was the bravest character in the Marvel Universe. The know-it-all Sheldon proposed that whoever had to give Wolverine a prostate exam was, indeed, the winner of that dubiously enviable title. Sheldon’s wrong on this one, though, and comic book urologists can relax – Wolverine won’t need the prostate exam.

Wolverine’s primary mutant power is his healing ability.* Healing is a job regulated by the immune system, so we can assume that Wolverine’s immune system is phenomenal, given his healing ability and his resistance to aging and illness. It is this superb immune system that will prevent a future storyline wherein Wolverine deals with a cancer diagnosis.

*Yes, Wolverine also has other mutant abilities, and his claws are awesome. However, without his healing ability, he would not have been able to tolerate the process of fusing “adamantium” to his bones, and the claws would then have remained bone claws and not the super-cool blades that are so emblematic of Wolverine.

The immune system, the body’s major defense system, is intimately involved in cancer. The two major arms of the immune system are the adaptive immune system, including T and B cells that can be considered the “special teams,” and the innate immune system, which is more like the ground troops. The ability to avoid adaptive response is a key feature of the success of cancerous cells. Were our immune systems as excellent as Wolverine’s, our adaptive immune systems would seek out and demolish cancer before it could take hold. Failure of the adaptive immune system to control cancerous cell growth is a phenomenon that has long interested researchers, and advances in that area are discussed in this excellent post by Heather. In essence, Wolverine’s immune response is what we aspire to achieve in the field of immuno-oncology by promoting T-cell activation and targeting of cancer cells.

Advances in immuno-oncology deal mostly in the adaptive immune system (T and B cells); however, the innate immune system plays an even more active role in tumor development. For decades, tumors have been described as “wounds that do not heal.”** Under normal circumstances, the presence of a wound activates the innate immune system, causing leukocytes such as macrophages to quickly migrate to the site of the wound and begin their work of healing. The healing process requires activation of these cells, initiating reparative processes including inflammation and angiogenesis – two key processes also seen in tumor microenvironments. The key difference between wound healing and cancer is that in time, wounds heal and activation and inflammation are resolved, allowing the immune cells to disperse away from the site, and everything returns to normal.

**Clearly, “wounds that do not heal” are an impossibility for Wolverine, who has survived grievous wounds and even being torn in half!

Cancer does not resolve. In cancer, the immune cells do not disperse. In fact, after the initial migration to the tumor cells, they are overwhelmed by inhibitory signals from the tumor cells that alter the the immune cells’ activation state. This reduces cell killing and instead tricks the immune cells into providing pro-growth cytokines*** that actually help the cancer cells proliferate, create new blood vessels, and invade new tissue. These immune cells not only do not destroy the tumor cells – they actively contribute to the microenvironment that helps to sustain and grow tumors. If the immune system is  the military of the body, the troops go in to do their job against the enemy (the cancer), but are then brainwashed and forced into supportive roles by that same enemy.

***The immune system is enormously complex. Cytokines can be pro-inflammatory, pro-growth, anti-inflammatory, anti-growth, and so on. to Add to the confusion, the same cytokines can have opposite effects under different circumstances, not all of which we understand. Macrophages in particular have different states of activation, which are still controversial, and produce different sets of cytokines depending on the state. There is even a still-debated state specific to the tumor microenvironment. We have a lot to learn!

This would never happen to Wolverine. With his supercharged immune system, cancer cells would be obliterated immediately and efficiently, the tumor’s inhibitor signals unheeded. His mutant power would protect him from the immune dysfunctions that we mere humans suffer in our fight against cancer. However, we’re catching up. The immune system remains somewhat of a mystery, our knowledge of it lagging behind that of other biological systems. But promising advances such as those in immunotherapy are revealing more and more how we might manipulate it to maybe, possibly, be just a little more like Wolverine.

Now, who wants to work on the adamantium claws?


Leave a comment

The New Skin “Fix”? A Bacterial Spritz

by Heather Lasseter, PhD, Medical Writer

The use of antibacterial soaps has long been controversial.  According to the FDA, these products are no more effective at preventing illness than ordinary soap and water, and research indicates they may confer bacterial drug resistance.

So what if we focused on preserving our skin’s natural bacterial community, instead of killing it off?Picture1

Lately, the role of the human microbiome has gained exposure, with a primary focus on how altering the gastrointestinal tract’s bacterial community may impact conditions like Crohn’s disease, diabetes, and even obesity.  Moving forward, understanding the microbiome of the skin may be equally important for regulating human health and disease.

Bacteria, viruses, and fungi – oh my! 

Don Bliss, National Cancer Institute Visuals Online

Don Bliss, National Cancer Institute Visuals Online

The human skin is the largest organ in the body and represents the first line of defense against invading pathogens. But this physical and chemical barrier is populated by its own inhabitants: a diverse collection of bacteria, viruses, and fungi that preferentially thrive in different habitats of the epidermis. These make up the skin’s “microbiota,” one component of the human body’s complex microbiome. Counting bacteria alone,  as many as 1 million microorganisms may inhabit just 1 square centimeter of skin, with distinct populations preferring moist, dry, or sebaceous (oil-producing) environments.

Bacteria commonly found on the skin (commensal bacteria) include Propionibacterium acnes, Staphylococcus epidermidis, Staphylococcus aureus, Corynebacterium diphtheriae, Corynebacterium jeikeium, and Pseudomonas aeruginosa. Under normal conditions, commensal skin bacteria are thought to be beneficial in defending against pathogenic bacteria. Commensal microbes may also either protect from or contribute to diseases like atopic dermatitis, psoriasis, acne, skin ulcers, and cancer.

The skin microbiome has evolved with the host organism, adapting to survive large desiccated regions, areas of acidic pH, the continual shedding of superficial cells, and the host’s immune response. As such, having the right commensal microbial community appears necessary for healthy skin. While acne has long been associated with P. acnes, research indicates acne lesions – in contrast to healthy skin – are additionally colonized by S. epidermidis and Corynebacterium. Similarly, skin samples from patients with psoriasis have higher concentrations of S. aureus compared with those from healthy subjects, but also lower levels of Propionibacterium species.

So what does this mean?

Our antibacterial soaps – not to mention modern cosmetics and hygiene products that change the skin’s natural microenvironment – may fundamentally alter the composition of our friendly bacterial community. According to Audrey Gueniche, a project director from L’Oréal quoted in the New York Times Magazine, buzz surrounding the skin microbiome “has revolutionized the way we study the skin and the results we look for.” And companies are taking note.

  • With global patents pending and issued, AOBiome is developing topical treatments that use ammonia-oxidizing bacteria to help replenish bacteria that naturally exist on the skin.
  • Scientists from the R&D team at L’Oreal are collaborating on research endeavors to develop skin products that increase so-called “good” strains of bacteria.

More research is necessary to fully understand the long-term implications of altering the skin’s microbial composition, but restoring healthy skin bacteria may provide a unique opportunity to treat serious skin disorders. Probiotics have gained popularity among health-conscious consumers keen on maintaining good gut flora. Perhaps the time has come to consider how we treat, and even cultivate, beneficial skin microbiota.


1 Comment

Is Adherence Your Prisoner’s Dilemma? Patients, Pills, and Game Theory

By Anna Lau, PhD, Medical Writer

Chronic diseases (eg, asthma, diabetes, hypertension) are persistent conditions that can be controlled but not cured. Without treatment, chronic diseases increase the risk of death, but with treatment, patients can enjoy fairly normal lives. Yet getting patients to take their medications as directed (adhere to a treatment plan) is a widespread problem. For example, direct costs of nonadherence to treatments for diabetes, hypertension, and hypercholesterolemia together exceed $105 billion annually in the US. It’s estimated that only 50% of patients with chronic conditions are adherent to treatment. What gives?

Can game theory shed light on poor adherence to chronic medication?

Game theory is the study of strategic decision-making. The prisoner’s dilemma is a well-known game of strategy that explores how two parties balance cooperation and competition in decision-making. Game theory has also been used to understand how decisions are made in conflict situations. By drawing an analogy to fighting a battle, let’s see what we might learn by applying conflict strategy to coping with a chronic disease. In his book The Strategy of Conflict (1960), Thomas Schelling suggests potential advantages to limiting one’s own options in a conflict situation. For example, in a hypothetical battle between grasshoppers and ants, a savvy ant general who positions its army at the edge of a cliff is more likely to win (Figure 1). Given the choice between certain death and fighting, the army ants are more likely to fight (and fight hard!).

The opposing grasshopper army is unlikely to charge forward and attack, because doing so would assure mutual destruction.
Figure 1

Figure 1. Army ants versus grasshoppers on a cliff.

But what if the choice were between fighting and something less than certain death (Figure 2)? Would the army ants fight as hard? Probably not.

Figure 2. Army ants versus grasshoppers near a mud pit.

Patients who experience acute illnesses of sudden onset and short course, such as heart attacks, may experience severe symptoms. And on average, about 15% of heart attacks are fatal. It’s hard to imagine that a patient in the midst of a heart attack would willfully refuse treatment. Given the choice between possible death and accepting treatment, patients are highly motivated to literally fight for their lives.

But patients with chronic conditions may not feel sick or experience overt symptoms most of the time. The motivation to faithfully take medications may be diminished, because the choice for them is between bearing the burden of chronic medication or living with an asymptomatic (or mildly symptomatic) condition. And if the medication causes side effects, or is painful to administer (like injections), inconvenient to take, or expensive, the choice may be easier. In addition, if effective rescue therapies are available, the motivation to adhere to chronic medication may be even lower. Patients might choose to take rescue medications occasionally over chronic medications daily.

Okay, now what about decision theory?

Decision theory explores factors that go into decision-making. It’s related to game theory, except that it focuses on how individuals, not multiple parties, make decisions. In their paper Choices, Values, and Frames (1984), Kahneman and Tversky describe loss aversion, the observation that people dislike losing something more than they like gaining something. For instance, Kahneman recounts asking students in his class to gamble on a coin toss. Given the condition that they would lose $10 if the coin toss turned up tails, how much money would they insist on winning in order to agree to gamble? The answer was usually more than $20. Loss aversion stems from the endowment effect, the tendency of people to value something more once they own it. For instance, if you ask home sellers and buyers to estimate the value that the other party would put on a home for sale, sellers tend to overestimate the value and buyers tend to underestimate. Loss aversion often leads to status quo bias, the preference of people to do nothing instead of making a change. In a set of experiments, people were more willing to accept an electric shock than take the chance of reducing that shock by pressing a button.

Asymptomatic patients may not be willing to change their current lifestyles to take chronic medications, even if the potential payoff is better health or delayed disease progression. This phenomenon has been termed “patient inertia.” Researchers believe that nonadherence to treatment may have less to do with lack of understanding of drug benefits and more to do with this tendency to do nothing (maintain the status quo).

Certainly there are other barriers to adherence…?

Of course, and those barriers include provider-related factors (eg, prescribing an overly complex regimen, failure to communicate effectively with the patient), patient-related factors (eg, poor understanding of disease or benefits/risks of treatment), and healthcare system–related factors (eg, access to insurance coverage or to medication). These factors affecting treatment adherence are better studied than factors related to game theory or decision theory. Given how applicable game theory and decision theory are in explaining economic behaviors, it may be worthwhile to further investigate their potential role in treatment adherence.

As the term “inertia” implies, patients can be coaxed to adopt new behaviors such as taking daily medication by making those behaviors routine, easier, and more accessible. For example, tie the act of pill-taking to a daily event, such as eating breakfast or brushing teeth. Prescribe preloaded syringes to eliminate a step in treatment administration. And (if safe) leave medicine bottles in easy reach instead of inside a medicine cabinet. These small changes in behavior can improve adherence and possibly save hundreds of millions of dollars or more each year in healthcare costs.

Follow

Get every new post delivered to your Inbox.