When can you have sex after a heart attack? Most doctors do not talk about it.

Each year in the United States about 720,000 people have heart attacks and about 124,000 people in the UK and 55,000 people in Australia will have them as well. Since the 1980s, survival rates from heart attacks have improved – a lot of people get them, but more and more people are surviving. A recent study of patients in Denmark showed that in 1984-1988 31.4% of patients died within a month of having a heart attack. From 2004-2008 this was down to 14.8%.

Once a patient has made it through a heart attack and begins to recover, they get advice from their doctors on what to do to stay healthy and get back to normal. That includes a lot of things – when to go back to work, when they can start traveling again and what to eat. But there is an important item that a lot of doctors don’t talk about: sex.

There are no universal guidelines for getting back to ‘normal’

Providing advice about lifestyle can be more challenging than prescribing standardized medications or smoking cessation because “normal” life differs widely among patients and requires individualized counseling.

For instance, scientific evidence from large-scale clinical trials isn’t always available to help the cardiologist decide the ideal time for when an individual patient should return to work. A software engineer might get different advice than a butcher or construction worker who has to lift heavy objects all day long. Physicians have to carefully estimate the patient’s capacity for physical activity as well as the physical demands of the job and be pragmatic about how long a patient can take time off from work.

Sex also requires this kind individualized counseling. New research shows that patients want to talk about sexual activity with their doctors, but that all too often that conversation never takes place.

Time for a heart-to-heart with your doctor.
Heart via Syda Productions/Shutterstock

 

Let’s talk about sex

A recent study conducted in 127 hospitals in the United States and Spain suggests that doctors are not very good at broaching the topic of sexual activity after a heart attack.

Researchers studied 2,349 women and 1,152 men who had suffered from a myocardial infarction (the medical term for a heart attack). This study focused on younger heart attack patients (ages 18-55) and asked them whether they had discussed sexual activity with their doctors. With younger patients talking about life after a heart attack is especially important. The loss of sexual activity or function is a major quality of life issue, and can affect intimate relationships, reproduction and lead to depression.

In the month following the heart attack, only 12% of women and 19% of men had some discussion with a doctor about sex. In the US, most patients reported that they initiated the discussion, whereas in Spain, most discussions were initiated by the doctor. This means that more than 85% of patients received no advice from their doctors regarding if and when they could resume sexual activity.

The study found that the vast majority of patients were sexually active in the year before their heart attacks, and they valued sexuality as an important part of life. They also felt it was appropriate for physicians to initiate the discussion about having sex again.

It is interesting that in the US, patients were more likely to bring up sex and men were given more restrictive advice, while in Spain, physicians were more likely to bring up the topic and more restrictive recommendations were given to women.

The study did not specifically study the motivations of the physicians but these differences suggest that cultural differences and gender affect the counseling in regards to sexual activity. Future research could potentially also study the physicians and help uncover how culture and gender influence the counseling process.

This lack of communication between doctors and patients was not due to the patients’ unease: 84% of women and 91% of men said that they would feel comfortable talking to their doctors about sex. What is even more concerning is that the 15% or so of patients who received counseling often got inaccurate recommendations.

Sex is exercise. But doctors don’t talk about it that way

Two-thirds of those who talked about sex with their doctors were told that they could resume sexual activity with restrictions like limiting sex, taking a “passive role” or keeping their heart rate down during sex. But here’s the thing: sex is exercise. And after a heart attack doctors routinely ask patients whether they can tolerate mild to moderate physical activity such as mowing the lawn or climbing up two flights of stairs without chest pain or other major symptoms.

The Scientific Statement of the American Heart Association (AHA) on sexual activity states that it is reasonable to resume sexual activity as early as one week after an uncomplicated heart attack. If there are complications after the heart attack such as feeling out of breath or experiencing persistent chest pain then these problems need to be addressed first. And in the AHA guidelines there is no mention of “passive roles” or keeping heart rates down during sex. These restrictions are also quite impractical. How are patients supposed to monitor their heart rates and keep them down during sex?

The kind of restrictions recommended by doctors in the study – and presumably by medical practitioners who weren’t polled – are not backed up by science and place an unnecessary burden on a patient’s personal life. Hopefully, after reading the results of this study, doctors will take a more pro-active role and address the topic of sex with their heart attack patients with proper recommendations instead of leaving patients in a state of uncertainty. If a patient can handle moderate exercise, they can probably handle sex.

The Conversation

This article was originally published on The Conversation.
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New Study Shows Surgical Checklists In Operating Rooms Are Less Effective Than Assumed

The patient has verified his or her identity, the surgical site, the type of procedure, and his or her consent. Check.

The surgical site is marked on a patient if such marking is appropriate for the procedure. Check.

The probe measuring blood oxygen content has been placed on the patient and is functioning. Check.

All members of the surgical and anesthesia team are aware of whether the patient has a known allergy? Check.

Surgeon
Surgeon – via Shutterstock

These were the first items on a nineteen-point World Health Organization (WHO) surgical safety checklist from an international research study to evaluate the impact of routinely using checklists in operating rooms. The research involved over 7,500 patients undergoing surgery in eight hospitals (Toronto, Canada; New Delhi, India; Amman, Jordan; Auckland, New Zealand; Manila, Philippines; Ifakara, Tanzania; London, England; and Seattle, WA) and was published in the New England Journal of Medicine in 2009.

Some of the items on the checklist were already part of standard care at many of the enrolled hospitals, such as the use of oxygen monitoring probes. Other items, such as ensuring that there was a contingency plan for major blood loss prior to each surgical procedure, were not part of routine surgical practice. The impact of checklist implementation was quite impressive, showing that this simple safety measure nearly halved the rate of death in surgical patients from 1.6% to 0.8%.  The infection rate at the site of the surgical procedure also decreased from 6.2% in the months preceding the checklist introduction to a mere 3.4%.

Checklists as a Panacea?

The remarkable results of the 2009 study were met with widespread enthusiasm. This low-cost measure could be easily implemented in hospitals all over the world and could potentially lead to major improvements in patient outcomes. It also made intuitive sense that encouraging communication between surgical team members via checklists would reduce complications after surgery.

A few weeks after the study’s publication, the National Patient Safety Agency (NPSA) in the United Kingdom issued a patient safety alert, requiring National Health Service (NHS) organizations to use the WHO Surgical Safety Checklist for all patients undergoing surgical procedures. In 2010, Canada followed suit and also introduced regulations requiring the use of surgical safety checklists. However, the data for the efficacy of such lists had only been obtained in observational research studies conducted in selected hospitals. Would widespread mandatory implementation of such a system in “real world” community hospitals also lead to similar benefits?

A recently published study in the New England Journal of Medicine lead by Dr. David Urbach at the University of Toronto has now reviewed the surgery outcomes of hospitals in Ontario, Canada, comparing the rate of surgical complications during three-month periods before and after the implementation of the now mandatory checklists.  Nearly all the hospitals reported that they were adhering to the checklist requirements and the vast majority used either a checklist developed by the Canadian Patient Safety Institute, which is even more comprehensive than the WHO checklist or other similar checklists. After analyzing the results of more than 200,000 procedures at 101 hospitals, Urbach and colleagues found no significant change in the rate of death after surgery after the introduction of the checklists (0.71% versus 0.65% – not statistically significant). Even the overall complication rates or the infection rates in the Ontario hospitals did not change significantly after surgical teams were required to complete the checklists.

 

Check the Checklist

 

The discrepancy in the results between the two studies is striking. How can one study demonstrate such a profound benefit of introducing checklists while a second study shows no significant impact at all? The differences between the two studies may hold some important clues. The 2009 study had a pre-checklist death rate of 1.6%, which is more than double the pre-checklist death rate in the more recent Ontario study. This may reflect the nature and complexity of the surgeries surveyed in the first study and also the socioeconomic differences. A substantial proportion of the patients in the international study were enrolled in low-income or middle-income countries. The introduction of a checklist may have been of much greater benefit to patients and hospitals that were already struggling with higher complication rates.

Furthermore, as the accompanying editorial by Dr. Lucian Leape in the New England Journal of Medicine points out, assessment of checklist implementation in the recent study by Urbach and colleagues was based on a retrospective analysis of self-reports by surgical teams and hospitals. Items may have been marked as “checked” in an effort to rush through the list and start the surgical procedures without the necessary diligence and time required to carefully go through every single item on the checklist. In the 2009 WHO study, on the other hand, surgical teams were aware of the fact that they were actively participating in a research study and the participating surgeons may have therefore been more motivated to meticulously implement all the steps on a checklist.

One of the key benefits of checklists is that they introduce a systematic and standardized approach to patient care and improve communication between team members. It is possible that the awareness of surgical teams in the Ontario hospitals in regards to patient safety and the need for systematic communication was already raised to higher level even before the introduction of the mandatory checklists so that this mandate may have had less of an impact.

 

Looking Forward

The study by Urbach and colleagues does not prove that safety checklists are without benefit. It highlights that there is little scientific data supporting the use of mandatory checklists. Since the study could not obtain any data on how well the checklists were implemented in each hospital, it is possible that checklists are more effective when team members buy into their value and do not just view it as another piece of mandatory and bureaucratic paperwork.

Instead of mandating checklists, authorities should consider the benefits of allowing surgical teams to develop their own measures that improve patient safety and team communication. The safety measures will likely contain some form of physical or verbal checklists. By encouraging surgical teams to get involved in the development process and tailor the checklists according to the needs of individual patients, surgical teams and hospitals, they may be far more motivated to truly implement them.

Optimizing such tailored checklists, understanding why some studies indicate benefits of checklists whereas others do not and re-evaluating the efficacy of checklists in the non-academic setting will all require a substantial amount of future research before one can draw definitive conclusions about the efficacy of checklists. Regulatory agencies in Canada and the United Kingdom should reconsider their current mandates. Perhaps an even more important lesson to be learned is that health regulatory agencies should not rush to enforce new mandates based on limited scientific data.

 

ResearchBlogging.org

Urbach DR, Govindarajan A, Saskin R, Wilton AS, & Baxter NN (2014). Introduction of surgical safety checklists in Ontario, Canada. The New England Journal of Medicine, 370 (11), 1029-38 PMID: 24620866

Should Doctors ‘Google’ Their Patients?

Here is an excerpt from my latest post on the 3Quarksdaily blog:

 

Beware of what you share. Employers now routinely utilize internet search engines or social network searches to obtain information about job applicants. A survey of 2,184 hiring managers and human resource professionals conducted by the online employment website CareerBuilder.com revealed that 39% use social networking sites to research job candidates. Of the group who used social networks to evaluate job applicants, 43% found content on a social networking site that caused them to not hire a candidate, whereas only 19% found information that that has caused them to hire a candidate. The top reasons for rejecting a candidate based on information gleaned from social networking sites were provocative or inappropriate photos/information, including information about the job applicants’ history of substance abuse. This should not come as a surprise to job applicants in the US. After all, it is not uncommon for employers to invade the privacy of job applicants by conducting extensive background searches, ranging from the applicant’s employment history and credit rating to checking up on any history of lawsuits or run-ins with law enforcement agencies. Some employers also require drug testing of job applicants. The internet and social networking websites merely offer employers an additional array of tools to scrutinize their applicants. But how do we feel about digital sleuthing when it comes to relationship that is very different than the employer-applicant relationship – one which is characterized by profound trust, intimacy and respect, such as the relationship between healthcare providers and their patients?


The Hastings Center Report is a peer-reviewed academic bioethics journal which discusses the ethics of “Googling a Patient” in its most recent issue. It first describes a specific case of a twenty-six year old patient who sees a surgeon and requests a prophylactic mastectomy of both breasts. She says that she does not have breast cancer yet, but that her family is at very high risk for cancer. Her mother, sister, aunts, and a cousin have all had breast cancer; a teenage cousin had ovarian cancer at the age of nineteen; and that her brother was treated for esophageal cancer at the age of fifteen. She also says that she herself has suffered from a form of skin cancer (melanoma) at the age of twenty-five and that she wants to undergo the removal of her breasts without further workup because she wants to avoid developing breast cancer. She says that her prior mammogram had already shown abnormalities and she had been told by another surgeon that she needed the mastectomy.

Such prophylactic mastectomies, i.e. removal of both breasts, are indeed performed if young women are considered to be at very high risk for breast cancer based on their genetic profile and family history. The patient’s family history – her mother, sister and aunts being diagnosed with breast cancer – are indicative of a very high risk, but other aspects of the history such as her brother developing esophageal cancer at the age of fifteen are rather unusual. The surgeon confers with the patient’s primary care physician prior to performing the mastectomy and is puzzled by the fact that the primary care physician cannot confirm many of the claims made by the patient regarding her prior medical history or her family history. The physicians find no evidence of the patient ever having been diagnosed with a melanoma and they also cannot find documentation of the prior workup. The surgeon then asks a genetic counselor to meet with the patient and help resolve the discrepancies. During the evaluation process, the genetic counselor decides to ‘google’ the patient.

The genetic counselor finds two Facebook pages that are linked to the patient. One page appears to be a personal profile of the patient, stating that in addition to battling stage four melanoma (a very advanced stage of skin cancer with very low survival rates), she has recently been diagnosed with breast cancer. She also provides a link to a website soliciting donations to attend a summit for young cancer patients. The other Facebook page shows multiple pictures of the patient with a bald head, suggesting that she is undergoing chemotherapy, which is obviously not true according to what the genetic counselor and the surgeon have observed. Once this information is forwarded to the surgeon, he decides to cancel the planned surgery. It is not clear why the patient was intent on having the mastectomy and what she would gain from it, but the obtained information from the Facebook pages and the previously noted discrepancies are reason enough for the surgeon to rebuff the patient’s request for the surgery.

 

If you want to learn more about how ethics experts analyzed the situation and how common it is for psychologists enrolled in doctoral programs to use search engines or social networking sites in order to obtain more information about their patients/clients, please read the complete article at 3Quarksdaily.com.  

Prescribing Male Contraceptives: Ethical Considerations

There have been a series of interesting comments on Twitter about the ethical dilemma involved in prescribing male contraceptives, prompted by my recent essay for Aeon Magazine. Here is the relevant excerpt from the Aeon essay:

The discontinuation of the WHO/CONRAD trial was a major setback in bringing male contraceptives to the market. It also raised difficult ethical questions about how to evaluate side effects in male contraceptive trials. Since all medications are bound to exhibit some side effects, what side effects should be sufficient to halt a trial? Female contraceptives have been associated with breakthrough bleeding, mood changes, increased risk of blood-clot formation, as well as other side effects. Why should we set a different bar for male contraceptives?

The twist here is that female contraceptives prevent unintended pregnancies in the person actually taking the contraceptive. Since a pregnancy can cause some women significant health problems, the risk of contraceptive side effects can be offset by the benefit of avoiding an unintended pregnancy. However, men do not directly experience any of the health risks of pregnancy — their female partners do. Thus it becomes more difficult, ethically, to justify the side effects of hormonal contraceptives in men.

The usage of female hormonal contraceptives has been associated with a higher risk of blood clot formation, but pregnancies carry an even higher risk for blood clot formation and other medical complications. Doctors can make the reasonable argument that the benefits of a contraceptive outweighs the risks for their patient – and prescribe it.

The situation is a bit different when it comes to male contraceptives. I will try to illustrate this with a hypothetical scenario, in which there is a male contraceptive on the market.

Mr. Solo has an appointment with his family physician Dr. Crusher, who informs him that he is in perfect health. Mr. Solo then asks if he could receive a prescription for the newly approved male contraceptive. Dr. Crusher explains to him that this new male contraceptive has a 1% risk of causing side effects such as major depression.

Mr. Solo responds that he and his partner Ms. Amidala-Skywalker have decided not to get pregnant – at least not in the near future. Mr. Solo is very concerned about Ms. Amidala-Skywalker’s family history because her mother had a very difficult pregnancy and even died during childbirth. Ms. Amidala-Skywalker is not as worried about her pregnancy as Mr. Solo is and she does not want either of them to be permanently sterilized, but she and Mr. Solo have agreed to at least postpone having children for a few years. Ms. Amidala-Skywalker has been on an oral hormonal contraceptive for the past years.

Just prior to seeing Dr. Crusher, Mr. Solo was browsing some reading material in the waiting room and came across the magazine “Women’s Health” in which he read that women who regularly use hormonal contraceptives are at a higher risk for blood clot formations and maybe even strokes. All these years, his partner has been taking hormonal contraceptives and exposing herself to this higher risk. Since they both agreed not to have children at this point in time, Mr. Solo feels that it would only be fair if he now started using a male contraceptive and gave his partner a break. He does not mind the 1% risk of side effects, after all, she has been taking the “pill” for so many years and he believes that a true partnership is based on an equitable sharing of risks.

Dr. Crusher tries to dampen his enthusiasm. She says that she respects his desire to be fair towards his partner and she also wants to be supportive of their decision not to have a baby. She understands their concerns about the health risks that Ms. Amidala-Skywalker would face if she became pregnant.

However, Dr. Crusher explains to Mr. Solo that she has a doctor-patient relationship only with him – not with his partner. Dr. Crusher feels comfortable prescribing a medication for a patient when the patient derives a net health benefit from it. She agrees that Ms. Amidala-Skywalker’s well-being is important, but the health of Mr. Solo’s partner (or of any other family member) is not her primary concern. She does not see how she can justify subjecting him to a 1% risk of side effects and declines to prescribe it.

 

I am not suggesting that this is the best way or the only way to analyze the ethics of prescribing a male contraceptive pill which has some side effects. Not everyone has to agree with Dr. Crusher’s choice to focus only on the risks and benefits for her patient and to ignore the greater good or the medical benefits for his partner. These are the kinds of ethical dilemmas that physicians have to grapple with when it comes to addressing the issue of side effects associated with male contraceptives. Concerns about such ethical dilemmas and potential legal repercussions can act as deterrents for physicians and pharmaceutical companies.

But this does not mean that we should abandon the quest for male contraceptives. Doctors perform cosmetic surgeries without any medical benefits, despite the fact that some of the procedures can result in major complications. Physicians prescribe Viagra for men without a clearly defined medical indication even though Viagra can cause significant side effects.

If patients, healthcare professionals and the general public can find ways to ethically justify the risks of cosmetic surgery, it should be possible to resolve the dilemmas surrounding the prescription of male contraceptives. Instead of just maintaining the status quo in which women shoulder most of the burden and responsibility of contraception, we have to educate ourselves about alternatives and address the scientific, medical, ethical, political and cultural obstacles that prevent the development of newer male contraceptives.

//storify.com/jalees_rehman/ethics-of-male-contraception.js[View the story “The Ethics of Prescribing Male Contraceptives” on Storify]

Good Can Come From Bad: Genetic Testing For The BRCA Breast Cancer Genes

Our ability to test for the presence of genetic mutations has become extremely cost-efficient and private companies, such as 23andMe now offer genetic testing for consumers who want to find out about their predisposition for genetic diseases. The results of such tests are sent directly to the consumers, without the involvement of genetic counselors or other healthcare providers. This has lead to a growing concern about how people will respond to finding out that they are carriers of mutations that predispose them to certain life-threatening diseases. Will the individuals be burdened by excessive anxiety? Will they tell their relatives and their healthcare providers that they carry mutations?

A study published in the new open access journal PeerJ addressed these questions by contacting male and female individuals who has received genetic testing by 23andMe for mutations in the BRCA genes which are strongly associated with breast cancer. The study “Dealing with the unexpected: consumer responses to direct-access BRCA mutation testing” by Uta Francke and colleagues (who are all employees of 23andMe) surveyed 16 women and 16 men who had received the news that they were carriers of BRCA1 or BRCA2 mutations, as well as control subjects who received the fortunate news that they did not carry any of the common BRCA mutations. Among the 16 women who tested positive (i.e. found out that they had a significant likelihood of developing breast cancer), none were extremely upset and six were either mildly or moderately upset. Surprisingly, nine mutation-positive women reported that they felt “neutral”.

The majority of the mutation-positive participants shared the test results with their spouses / partners or their blood relatives. Importantly, 13 of the 16 mutation-positive women contacted their primary care physician, gynecologist or oncologist for medical advice. There were 11 mutation-positive women who received this information through 23andMe for the first time (the others had already been diagnosed with breast cancer or had previously undergone testing), and these women indicated that they were planning to either undergo surgeries or have further breast cancer work-up and regular exams. The majority of mutation-positive men, on the other hand, did not consult their physicians, but did indicate that they would participate in future cancer screening.

Nearly all the participants said that they would undergo the testing again and felt good about knowing the results, independent of whether they positive or negative for the BRCA mutations. Only one of the participants (a mutation positive man with a family history of breast cancer) said that he would have preferred not to know, because of the “emotional cost”. A significant proportion of the participants who tested positive also had their relatives tested. This lead to the identification of 13 additional carriers, many of whom received medical counseling and were planning to take risk-reducing measures.

These findings suggest that the identification of mutations that indicate a high risk for developing breast cancer did not lead to severe anxiety or panic, but actually resulted in pro-active steps and medical care to help reduce their risk of developing breast cancer. One has to bear in mind that the sample size is small and that the study and the salaries of the authors were all funded by 23andMe, a genetic testing company that would financially benefit from widespread genetic testing. Nevertheless, the presented data seem solid and the responses of the participants do suggest that such testing was on the whole very beneficial for the participants. Hopefully, we will see more data emerge in the future regarding the psychological impact of genetic testing and whether the findings of this small study hold up in larger cohorts and when it comes to other genetic diseases.

On a side note, there is a very intriguing aspect to this paper that will be of benefit to many readers. The PeerJ journal gives the authors of a manuscript the option of disclosing the peer review process to the public. The authors of this paper took advantage of this option and we can all have a close look at the peer reviewer comments as well as the rebuttal of the authors. For anyone who is not used to reviewing scientific manuscripts, this is an excellent opportunity to learn about the inner workings of the peer review process.

 

Image Credit: Cartoon representation of the molecular structure of BRCA1 by Jawahar Swaminathan and MSD staff at the European Bioinformatics Institute, via Wikimedia Commons

ResearchBlogging.org

Francke, U., Dijamco, C., Kiefer, A., Eriksson, N., Moiseff, B., Tung, J., & Mountain, J. (2013). Dealing with the unexpected: consumer responses to direct-access BRCA mutation testing PeerJ, 1 DOI: 10.7717/peerj.8

Flipping the Switch: Using Optogenetics to Treat Seizures

Optogenetics is emerging as one of the most exciting new tools in biomedical research. This method is based on introducing genes that encode for light-sensitive proteins into cells. A laser beam can then be used to activate the light-sensitive proteins. Many of the currently used optogenetic proteins respond to the laser activation by changing the membrane voltage potential inside the cells. This is the reason why neurons and other cells that can be excited by electrical impulses, are ideally suited for studying optogenetic responses.

The recent paper “On-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy” by Esther Krook-Magnuson and colleagues in Nature Communications (published online on January 22, 2013) applies the optogenetic approach to treat seizures in mice. The researchers used mice that had been genetically modified to express the inhibitory light sensitive protein halorhodopsin (normally only found in single cell organisms but not in mammals) in neurons. They placed an optical fiber to deliver the laser light to an area of the brain where they chemically induced a specific type of seizures (temporal lobe epilepsy or TLE) in the mice.

The results were quite remarkable. Activation of the laser light reduced the seizure duration by half within just five seconds. Krook-Magnuson and colleagues then also chose a second optogenetic approach to treat the seizures. Instead of using mice that contained the inhibitory light-sensitive protein halorhodopsin, they opted for mice with the excitatory (activating) light-sensitive protein channelrhodopsin (Chr2). This may seem a bit counter-intuitive, since the problem in epilepsy is that there is too much activation of neurons. One would not necessarily want to introduce activating light-sensitive proteins into neurons that are already too active. The key to understanding their strategy is the choice of the target: a subset of GABAergic cells, which can inhibit the seizure activity in neighboring neurons. This second approach was just as effective as the first approach, which used the halorhodopsin protein.

This means that one can substantially cut down seizure duration by more than half, either by directly inhibiting seizing neurons, or by activating inhibitory neurons. This research shows that there is tremendous potential for developing novel optogenetic treatments for epilepsy. Specifically targeting selected neurons that are involved in seizure activity would be preferable to generalized treatment with medications that affect global neuronal activity and could cause side effects (as is often the case with current epilepsy medications).

It is not yet clear whether this treatment can be easily applied to humans. The linchpin of the experiment was genetically introducing the light-sensitive proteins into selected neurons of the mice. This type of targeted neuronal gene therapy would be far more difficult in humans. The other obstacle is that the light activation in the mice required implantation of an optical fiber which directed the light into a specific area of the brain. Performing such an invasive procedure in patients could carry potential risks that would need to be carefully balanced with the risks and benefits of just continuing to use anti-seizure medications. Hopefully, future improvements in gene therapy methods and light stimulation will be able to help overcome these obstacles and pave the way for a whole new class of optogenetics-based therapies in patients with epilepsy and other neurological disorders.

 

Image credit: Confocal image of an eGFP filled striatal medium spiny neuron, National Institutes of Health (NIH), Margaret I. Davis

ResearchBlogging.org
Krook-Magnuson, E., Armstrong, C., Oijala, M., & Soltesz, I. (2013). On-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy Nature Communications, 4 DOI: 10.1038/ncomms2376

Immune Cells Can Remember Past Lives

The generation of induced pluripotent stem cells (iPSCs) is one of the most fascinating discoveries in the history of stem cell biology. John Gurdon and Shinya Yamanaka received the 2012 Nobel Prize for showing that adult cells could be induced to become embryonic-like stem cells (iPSCs). Many stem cell laboratories now routinely convert skin cells or blood cells from an adult patient into iPSCs. The stem cell properties of the generated iPSCs then allow researchers to convert them into a desired cell type, such as heart cells (cardiomyocytes) or brain cells (neurons), which can then be used for cell-based therapies or for the screening of novel drugs. The initial conversion of adult cells to iPSCs is referred to as “reprogramming” and is thought to represent a form of rejuvenation, because the adult cell appears to lose its adult cell identity and reverts to an immature embryonic-like state. However, we know surprisingly little about the specific mechanisms that allow adult cells to become embryonic-like. For example, how does a blood immune cell such as a lymphocyte lose its lymphocyte characteristics during the reprogramming process? Does the lymphocyte that is converted into an immature iPSC state “remember” that it used to be a lymphocyte? If yes, does this memory affect what types of cells the newly generated iPSCs can be converted into, i.e. are iPSCs derived from lymphocytes very different from iPSCs that are derived from skin cells?

There have been a number of recent studies that have tried to address the question of the “memory” in iPSCs, but two recent papers published in the January 3, 2013 issue of the journal Cell Stem Cell provide some of the most compelling proofs of an iPSC “memory” and also show that this “memory” could be used for therapeutic purposes. In the paper “Regeneration of Human Tumor Antigen-Specific T Cells from iPSCs Derived from Mature CD8+ T Cells“, Vizcardo and colleagues studied the reprogramming of T-lymphocytes derived from the tumor of a melanoma patient. Mature T-lymphocytes are immune cells that can recognize specific targets, depending on what antigen they have been exposed to. The tumor infiltrating cells used by Vizcardo and colleagues have been previously shown to recognize the melanoma tumor antigen MART-1. The researchers were able to successfully generate iPSCs from the T-lymphocytes, and they then converted the iPSCs back to T-lymphocytes. What they found was that the newly generated T-lymphocytes expressed a receptor that was specific for the MART tumor antigen. Even though the newly generated T-lymphocytes had not been exposed to the tumor, they had retained their capacity to respond to the melanoma antigen. The most likely explanation for this is that the generated iPSCs “remembered” their previous exposure to the tumor in their past lives as T-lymphocytes before they had been converted to embryonic-like iPSCs and then “reborn” as new T-lymphocytes. The iPSC reprogramming apparently did not wipe out their “memory”.

This finding has important therapeutic implications. One key problem that the immune system faces when fighting a malignant tumor is that the demand for immune cells outpaces their availability. The new study suggests that one can take activated immune cells from a cancer patient, convert them to the iPSC state, differentiate them back into rejuvenated immune cells, expand them and inject them back into the patient. The expanded and rejuvenated immune cells would retain their prior anti-tumor memory, be primed to fight the tumor and thus significantly augment the ability of the immune system to slow down the tumor growth.

The paper by Vizcardo and colleagues did not actually show the rejuvenation and anti-tumor efficacy of the iPSC-derived T-lymphocytes and this needs to be addressed in future studies. However, the paper “Generation of Rejuvenated Antigen-Specific T Cells by Reprogramming to Pluripotency and Redifferentiation” by Nishimura and colleagues in the same issue of Cell Stem Cell, did address the rejuvenation question, albeit in a slightly different context. This group of researchers obtained T-lymphocytes from a patient with HIV, then generated iPSC and re-differentiated the iPSCs back into T-lymphocytes. Similar to what Vizcardo and colleagues had observed, Nishimura and colleagues found that their iPSC derived T-lymphocytes retained an immunological memory against HIV antigens. Importantly, the newly derived T-lymphocytes were highly proliferative and had longer telomeres. The telomeres are chunks of DNA that become shorter as cells age, so the lengthening of telomeres and the high growth rate of the iPSC derived T-lymphocytes were both indicators that the iPSC reprogramming process had made the cells younger while also retaining their “memory” or ability to respond to HIV.

Further studies are now needed to test whether adding the rejuvenated cells back into the body does actually help prevent tumor growth and can treat HIV infections. There is also a need to ensure that the cells are safe and the rejuvenation process itself did not cause any harmful genetic changes. Long telomeres have been associated with the formation of tumors and one has to make sure that the iPSC-derived lymphocytes do not become malignant. These two studies represent an exciting new development in iPSC research. They not only clearly document that iPSCs retain a memory of the original adult cell type they are derived from but they also show that this memory can be put to good use. This is especially true for immune cells, because retaining an immunological memory allows rejuvenated iPSC-derived immune cells to resume the fight against a tumor or a virus.

 

Image credit: “Surface of HIV infected macrophage” by Sriram Subramaniam at the National Cancer Institute (NCI) via National Institutes of Health Image Bank