The dead, the headlines read, might soon be brought back to life.
As pop-science headlines tend to, they blew the actual research proposal out of proportion, but the premise is real: The ReAnima Project recently received “ethical permission” from the government of India to take 20 patients who’ve been declared clinically brain dead, and try to restore a limited range of brain functions using cutting-edge neuroscience techniques.
When we get past the knee-jerk references to zombies and Dr. Frankenstein, though, we’re left with the question of what this research is really about. Can scientists actually bring brain-dead patients back to life? Has anyone tried it before? And what does it mean, exactly, to resurrect a brain dead person? Read More
Elizabeth (Liz) Parrish is the CEO of BioViva, a biotechnology company that focuses on developing gene therapies, and other regenerative therapies, to intervene with human aging.
Last September, Parrish added an interesting line to her job description: patient zero for two anti-aging therapies that the company is researching.
Parrish is receiving two kinds of injections, which are administered outside the United States: a myostatin inhibitor, which is expected to prevent age-associated muscle loss; and a telomerase gene therapy, which is expected to lengthen telomeres, segments of DNA at the ends of chromosomes whose shortening is associated with aging and degenerative disease.
The study will likely continue for many years. But last week, BioViva issued a press release describing an unexpected early result, offering a clue as to what the BioViva team might publish in the weeks or months to come.
It will be unclear exactly what the BioViva researchers have found until the results do go through the rigorous process of scientific peer-review, but the un-reviewed BioViva report is raising some eyebrows. Telomeres of T-lymphocytes in blood samples taken from Parrish in September were 6.71 kilobases. That’s shorter than normal for Parrish’s age, but lymphocytes from the samples taken in March after six months of gene therapy measured 7.33 kb, according to BioViva.
The company equates the reported 620-base increase to reversing the clock on Parrish’s chromosomes by twenty years. But there are numerous caveats noted by experts in genetics and laboratory medicine that were recently published by the non-profit group Genetics Expert News Service.
For one thing, telomeres are being tested only in her T-lymphocytes, as opposed to all tissue types of her body, so even if the test result were evidence for de-aging of T-lymphocytes it doesn’t necessarily prove her entire body de-aged.
“Long-lived T cells have shorter telomere lengths than newly generated naïve cells; and cells which have reached their maximum limit of cell divisions have shorter telomeres than any other cell type,” says Rita Effros, a professor of pathology and laboratory medicine at UCLA. “Thus, a simple change in the proportion of different cell types within the peripheral blood could easily explain the data.”
Furthermore, notes Dr. Bradley Johnson, Associate Professor of Pathology and Lab Medicine at the University of Pennsylvania, “Telomere length measurements typically have low precision, with variation in measurements of around 10 percent, which is in the range of the reported telomere lengthening apparently experienced by Elizabeth Parrish.”
These criticisms notwithstanding, Parrish serving as patient zero for a brand new treatment is a milestone in medicine, one that harkens back to the medical pioneers who regularly injected themselves with various new drugs over a century ago. Before BioViva’s news broke, Discover’s Dr. David Warmflash interviewed Parrish about the therapies and her feelings about being the first test subject.
Discover: What would you say makes BioViva stand out from other biotech or gene therapy companies? Is it that you’re using yourself as a test subject?
Liz Parrish: Yes, and number two is treating biological aging as a disease. Actually, that is probably number one. We’re going at the root cause of what makes most of the population sick. And then second, of course, we’re 100 percent behind the product.
We’re using them. We are not just a research company. BioViva is about saving lives, and lessons from history suggest that the use of multiple experimental therapies at once may be the shortest route to saving lives. When AIDS research first began, we saw the use of many drugs which, when used in isolation, helped with one mechanism of the disease, but patients still died from another mechanism of the same disease. It was only when doctors combined those drugs into cocktails we saw the first real advances in combating AIDS.
Do you feel any connection, or do you see yourself as carrying on a tradition of the those early medical researchers from the late 19th and early 20th century who tested different drugs on themselves?
LP: Yes, I guess so in retrospect. We didn’t do it in the spirit of that. We did it because it had to be done, because we needed a test patient on the gene therapy, but I think it is in that spirit and I wish more people had that spirit. The U.S. is 5 percent of the world population. We take 75 percent of all prescription drugs and yet have the shortest lifespan of every industrialized country, so I wish more people would get behind their drugs and other therapies. I think it would prove that what they have is something that you would want to take.
OK, so let’s talk about the therapies that you’re taking. Is there any concern the telomerase gene therapy could led to malignancy, to cancer, in any tissue?
LP: Telomerase has never been hypothesized to be the sole cause of cancer. Not all cancers have telomerase upregulated in them. Cancer cells can develop daily in your body from a very young age. But isn’t a youthful immune system is what keeps full-blown cancer at bay?
The confusion of longevity research with cancer research is a recurring misconception and implies correlations that have not been proven. There are two lines of research into telomerase: longevity and cancer. The two never intersect.
In longevity research we do not find ourselves looking at increases in cancerous cells from telomerase induction, but rather a protection against cancer.
In previous interviews with other people, you’ve alluded to the tragic story of Jesse Gelsinger, the 18-year-old boy who died in an early gene therapy clinical trial at the University of Pennsylvania in the 1990s.
Ethically, of course there’s a difference between Gelsinger and you; I’ve heard you say that this is worth risking your life for. But on top of the tragedy of Gelsinger losing his life, didn’t it also set the whole field of gene therapy back several years?
From that perspective, in the unlikely event that something goes terribly wrong in the experiment on you, do you worry what might happen to gene therapy research? Have you considered this a possible rationale for slowing down, maybe taking a more conservative approach?
LP: Gene therapy has come a long way since the 1999 tragedy of Jesse Gelsinger.
The relevant research did not stop [after the event], only the applications, and even then only temporarily. But the big game-changer now is that we have better delivery methods.
Hundreds of people are partaking in gene therapies today and none have the issues we saw 16 years ago in Jesse Gelsinger. We also need to put this in perspective: almost 100,000 people already die of adverse drug reactions (ADEs) every year in the USA alone, while nobody has ever died from this latest generation of gene therapies.
That being said, we at BioViva are very careful to ensure the safest possible outcome while still testing every limit. I would not have taken a gene therapy that would have likely killed the patient and nor would anybody at BioViva. I simply stated that all data are equally important, and that to that end I would accept any outcome, up to and including my own death, in order to move the science forward.
We as a company, and I as a person did take a risk, but a risk we believe will change the world for the better and kick-start an industry with the best approach to curing disease and increasing healthy lifespan.
What do you think about the idea that, the potential of the studies on you notwithstanding, you’re just one datum, so what will we really know?
LP: Yes, absolutely. That’s true, but N=1 from one human is worth 10,000 mice, but of course every human’s body is different and people are going to respond differently.
And of course the FDA since the 1970s has passed almost 50 drugs through the system to the market that it pulled later, despite going through gold standard testing. So that’s why we have to start now and see what happens. No matter what safety and efficacy you have, if you can have N=10,000, you’re probably going to have some adverse effects down the road.
Whether it’s directly related to the gene therapy or to something else in the patient’s life, it may take years to determine, so it’s very important to start now with gene therapy. Currently, over 100,000 people die of aging related diseases, so at what point do we realize that life is risky and that taking a chance may be our best bet?
Which tissues are they using to monitor your telomere length, given that telomeres vary between tissues? Generally, in telomere studies, lymphocytes are used, because they’re easy to access, but what factors went into deciding which tissues to use in you both for monitoring and targeting the therapy.
LP: We are using lymphocyte testing at this time, as it is the most advanced and well understood way to test telomere length today.
I also understand that to carry the therapeutic gene through your blood and into your cells, BioViva is using what’s called an AAV vector, which has the advantage of delivering the genetic payload so that it ends up as an episome (free floating gene), rather than being integrated into a chromosome.
Is this a safety measure, to minimize the risk of mutagenesis and oncogenic transformation? Is there any possible negative to that, such as decreased duration of the effects?
LP: We are not necessarily trying to integrate the gene, as studies have not proven the benefit of doing so.
We are trying to create an episome in the nucleus, which will code for the target protein. Integration is still an important discussion because past delivery methods, which we avoid due to them creating integrational mutagenesis (integrating into the chromosome in random areas that caused the cell to become unstable).
We want to separate our method from that older method. Our delivery method does not cause integrational mutagenesis, and when it does integrate, it does so into a safe harbor site on chromosome 19 where cancer is not an outcome.
Are there concerns among your team that treatment for slowing or reversing aging of healthy tissues could also prevent elimination of malignant or premalignant cells?
LP: Cancer cells can appear in people of any age, but the proliferation of cancer cells owes more to a decrease in immune system capability than an increase in telomerase activity. Not all cancers involve telomerase production, and a peer-reviewed paper in 2012 showed that old mice saw no increase in cancer with telomerase induction.
Telomerase induction may actually be our first line of defense against cancer, because a youthful immune system regularly rids the body of cancerous cells. The mechanism of telomerase could restore cells epigenetically to a youthful state exhibiting fewer aging gene biomarkers. An example would be turning off the genes that turn on as we age such as P53, a tumor-associated gene.
If you were to develop a common type of cancer, how would we know if it’s from the gene therapy, or because you would have gotten it anyway?
LP: If I was to be diagnosed with cancer, we could have that cancer sequenced to see if it had an extra copy of the target gene [from the gene therapy].
So, you’re getting telomerase gene therapy as well as a myostatin inhibitor. Was there any discussion about the merits of giving you two experimental therapies at the same time? Imagine it’s the year 2096, you’re 120 plus, looking and feeling exactly as you do today and you have the blood chemistry of a 25 year-old. How would we know which therapy did it?
LP: Such an amazing outcome, if it happened, would necessarily be due to both those two therapies or more.
We believe that these two types of therapy are synergistic, and will benefit each other in ways that will maximize outcome. One gene therapy is hypothesized to create better signaling with stem cells. The other creates stem cells that can potentially divide indefinitely, as stem cell depletion is a risk for older people.
These benefits, combined with the protection against frailty or sarcopenia (loss of muscle tissue) with a myostatin inhibitor, and the more youthful epigenetics of a cell with telomerase induction, makes this combined therapy very powerful.
Sprinkling “Omm” mantras between “Ooh Rah!” battle cries can pay dividends for members of the Marine Corps and other branches of the military. According to a growing body of research, regular meditation improves the wellbeing of military members — both active duty and those who have previously served.
Meditation is rooted in spirituality, which affects personal wellness in its own way, but the neurological underpinnings of meditation’s other health benefits are being widely assessed by researchers, and they’re building a scientific case for its benefits. Read More
Exactly why so many humans choose monogamous pair bonds over juggling multiple partners has long been a mystery to scientists. After all, having several partners at the same time should lead to more offspring — an outcome you’d think evolution would favor. Now a new study has linked the phenomenon to sexually transmitted diseases, arguing that monogamy could have evolved because it offered protection against the threat of infection.
Monogamy is, of course, the norm in Western societies. But there are many cultures where a husband can have more than one wife (polygyny) or, less commonly, a wife can have more than one husband (polyandry). This diversity of human mating systems is also hard to explain. What we do know, however, is that many hunter-gatherer societies, living in small groups, were most often polygynous (and many remaining groups still are). But with the rise of agriculture, societies tended to become more complex — and less polygynous. In the most strictly monogamous societies, there was often a social punishment for polygynists, either informally or, as in many modern societies, through a legal system. Read More
They scrub in according to a strict protocol. All instruments are sterile, the patient is put to sleep, and an incision is cut and held open with retractors. Moving into the abdominal cavity, surgeons clamp bleeding arteries and cauterize tissues meticulously to prevent blood loss while also making the surgical field easier to see.
Thus far, it seems just like surgery today, but for the numerous people overlooking from elevated theater seats, dressed in formal Victorian outfits. That’s the operating room setting on the Cinemax period medical drama, The Knick. There are a host of other details that make the setting look ancient, but the differences from modern surgery are most striking when things start going wrong.
For instance, the patient’s heart rate becomes rapid, then erratic, and the surgeon knows this only because of a nurse listening to the patient with a stethoscope. She can’t report blood pressure, because no device is set up to measure it — there are no monitors of any sort. Those devices don’t exist in the era when The Knick is set, nor would they help much, since the time period denies doctors even the most basic tools of resuscitation. The year is 1900, when many basic principles of surgery have been developed, but safe transfusions, electrocardiography, and other vital tools still lay several years into the future. Read More
Zika virus caught the world off guard, but it shouldn’t have.
The rapid spread of the mosquito-borne virus, and its possible connection to birth defects and neurological disorders, compelled the World Health Organization on Monday to declare an international public health emergency. But by that time 1.5 million Brazilians had already caught the virus, and it had spread to 24 countries in the Western Hemisphere. The current tally from the Centers for Disease Control and Prevention indicates 30 countries are now reporting active transmission.
“It seems like we are always behind,” says Jorge Osorio, a professor of infectious diseases at the University of Wisconsin-Madison. Osorio returned to the United States on Friday after a research stint in Colombia, where the total of confirmed Zika cases is second only to Brazil. “We knew it was a matter of time before this would happen.”
There’s no doubt that a rapid global response — like what’s currently underway — is needed, but Zika’s transformation from a sleeping virus to a global crisis is all too familiar. Since the 1970s, global re-emergence of mosquito-borne infectious diseases has only accelerated. In 2001, global cases of dengue fever skyrocketed. In 2004, chikungunya re-emerged in East Africa and spread worldwide. But with every new outbreak, a recurring flaw in the approach toward infectious disease control is exposed: We’re consistently reactive.
“It’s sort of human nature. We react to the thing that’s on fire, but we aren’t so good at prevention,” says David Katz, a certified board specialist in public health and founding director of Yale University’s Yale-Griffin Prevention Research Center. “We neglect the factors that produce emerging infectious disease, and in the blink of an eye we have a global crisis on our hands.”
By the late 1960s humanity was winning its war with malaria, yellow fever, dengue and a host of other diseases. Proactive, aggressive eradication efforts eliminated the Aedes aegypti mosquito — the primary carrier of infectious diseases — in 23 countries. But our declaration of victory was specious.
Duane Gubler, a professor of emerging infectious diseases at Duke-NUS Medical School in Singapore, noted in a 2011 review that our comfort in victory kicked off a period of “increasing apathy and complacency” toward controlling infectious diseases. A new, more reactive paradigm of surveillance and emergency response was adopted for disease control, and resources shifted to other diseases.
In the four decades that followed, unprecedented population growth occurred around the world, and more people converged in crowded urban centers. Mosquitoes that once spread diseases in remote, less-populated locales had millions more human hosts to bite and infect in confined areas. On top of that, advances in global transportation made the world smaller and further enhanced the ability of viruses to expand their reach. Today, a respond-to-an-emergency approach can’t keep up with the ability of viruses to mutate and spread.
“We live in a crisis-oriented society. But this has been going on for the better part of 40 years as we’ve seen these global pandemics of infectious diseases spread,” says Gubler. “We wait for them to occur.”
Infectious disease researchers could see Zika’s warning signs long before the outbreak captured headlines. The virus was isolated in 1947 from rhesus monkeys in Uganda. Only sporadic human Zika infections were reported since its initial discovery, and its clinical presentation didn’t sound alarms. Oftentimes, infected people wouldn’t know Zika was in their system. For that reason, the virus didn’t garner much attention or warrant funding for research.
“In the United States, research for all science and infectious diseases has been at historic lows, so to get funding for Zika virus, which wasn’t causing many infections, was nearly impossible,” says Matthew Aliota, a research scientist at the UW-Madison School of Veterinary Medicine.
It wasn’t until 2007 that a Zika epidemic swept through Yap Island in the Federated States of Micronesia. A larger epidemic followed in French Polynesia in 2013-14. In May 2015, the Pan American Health Organization issued an alert about the transmission of Zika virus in Brazil. And in July, Gubler sounded the warning in an issue of The Lancet.
“We essentially predicted this months ago, and said it would follow in the footsteps of chikungunya because it has the same epidemiology,” says Gubler. “Part of our problem is that we have a mentality of looking at these viruses, including a lot of virologists, as monolithic species. These viruses change genetically, and those changes affect expression.”
Today, a virus that was largely ignored is now affecting human health in ways we didn’t anticipate. In other words, a virus that’s lying dormant doesn’t make it less of a threat to world populations. And with half the world’s population living in areas susceptible to infectious diseases, a virus that’s gone quiet doesn’t mean it won’t come roaring back.
“Yellow fever is another virus that’s sitting in the wings. It still exists in West Africa, but it’s been relegated for the past 60 years,” says Gubler. “If, or when, it starts causing trouble, it will make all of these other outbreaks pale by comparison.”
That’s why Gubler, Osorio, Katz and others advocate for going on the offensive to strike viruses before they spiral out of control — even benign viruses. With adequate resources, vaccine development could be accelerated. Mosquito populations could be kept in check. Researchers across scientific disciplines could collaborate to build ways to predict future hotspots for outbreaks and focus energies there.
“You need to rebuild public health infrastructure in endemic countries and develop the lab capacity to support a surveillance system to give you some predictive capability,” says Gubler. “That requires investment, dedication and some bit of faith on the part of policymakers that this is money well spent.”
Osorio and Aliota are working in Colombia to build more accurate laboratory diagnoses of Zika, dengue and chikungunya. The other focus of their research is to track the way Zika and viruses like it evolve and adapt in their hosts. Their research has shown that Zika split into two distinct lineages, African and Asian. The strain they’re seeing in Colombia can be traced back to the strain that existed in the 2013-14 outbreak in French Polynesia. But their work has a larger aim: predicting how viruses will mutate to get ahead of the next outbreak.
“I’m trying to be more predictive using lab studies and experimental evolution in the lab to be more proactive,” says Aliota. “It’s idealistic thinking, but we’re working to predict the evolvability and adaptability of certain viruses.”
Building a more thorough global network of early detection centers around the world is also essential for pivoting to a proactive approach to infectious disease. Expanding the reach of organizations like the Global Virus Network, which is composed of research centers around the world that focus on viral causes of human disease to prepare for novel pandemic threats, could provide enough warning stay ahead. A robust, global virus detection system could operate similarly to the global array of earthquake-detecting instruments that give advance notice of a potential disaster.
“We must continue to create those centers around the world, and ensure they are funded and equipped with people who are well trained to do this,” says Osorio. “Early indication is important, and it gives us the ability to take measures right away.”
“We need to look at culture, epidemiology, economics and ecology at a local level and develop strategies from there,” says Gubler, who helped form the Partnership for Dengue Control, which brings health experts together to do that.
Overall, infectious disease researchers are pushing toward a more interdisciplinary approach to predict outbreaks. Jonathan Patz, director of the Global Health Institute at UW-Madison, is doing research to connect the dots between climate change and global health, offering a glimpse into the ways differing scientific fields can combine to build a proactive approach to mosquito-borne disease. His research has revealed a link between dramatic climactic shifts and the occurrence of viral outbreaks.
“Extreme drought conditions tend to drive the proliferation of Aedes aegypti. Epidemics of Zika, dengue and chikungunya have been preceded by drought,” says Patz. “This year, the el Nino event is looking like the strongest on record. During el Nino, northeastern brazil is generally affected with drought.”
Patz notes there are myriad other variables that shift weather patterns and the spread of disease. But, generally speaking, he is finding that drought is a contributing factor. Patz’s work reflects a larger shift toward looking beyond the infectious agent and building a broader recognition of factors that are in play.
“It’s getting much better in terms of interdisciplinary focus,” says Aliota. “I never thought, when I first got into the hard sciences, that I would be talking to geographers, anthropologists and the other disciplines in my work.”
Of course, controlling the populations of A. aegypti, the source of the problem, is also a key area of research. Methods of population control, and wider access to mosquito nets and repellant in poor countries are essential. There’s also emerging interest in research to genetically modify mosquitoes. The research could limit their ability to breed — or wipe them out completely.
“Mosquito control has been left wanting for over 40 years, and that’s catching up with us,” says Gubler.
If there’s any silver lining from the surge in outbreaks, it’s that it brings into sharp focus the sheer connectedness of humanity. Zika, dengue and chikungunya don’t respect political borders. Outbreaks are forcing us to break long-standing lines of division and embrace the fact that we are one species.
“Zika does not give a damn about whether you are Muslim, Jewish or Christian,” says Katz. “The world is small, and there is no ‘over there anymore.’ We’re all in the same petri dish. I think that shift in thinking is fundamental to our preparedness.”
Millions of people are suffering from post-traumatic stress disorder (PTSD) right now. Among military personnel who’ve been deployed to Iraq and Afghanistan, an estimated 31 percent are PTSD sufferers. An estimated 52 percent of people with PTSD also suffer from major depressive disorder (MDD).
The cost of treating these disorders is estimated to run as high as $40 billion per year. The social consequences are harder to quantify, but many PTSD and MDD sufferers report marital problems, difficulties bonding with family and friends, and chronic suicidal thoughts.
But a team of researchers led by Andrew Leuchter, professor of psychiatry and biobehavioral sciences at UCLA, believes it has found a new treatment for PTSD and MDD. It’s not a new drug or a new form of psychotherapy. It’s a form of electronic nerve stimulation. Read More
In a 1978 essay, titled Where Am I?, the philosopher Daniel Dennett suggested that the brain was the only organ of which it’s better to be a transplant donor than recipient. Now Italian neurosurgeon Sergio Canavero wants to turn philosophical thought experiments into reality by transplanting the head of Valery Spiridonov, who suffers from a debilitating muscle wasting disease, onto the healthy body of a dead donor.
Beside posing questions about personal identity, there are more prosaic challenges that must first be overcome. The brain would have to be kept alive during surgery by cooling it to 10-15°C, and the immune system would need to be powerfully suppressed to prevent transplant rejection. But the greatest hurdle may be how to restore connections to the spinal cord. Without this connection the brain would have no control of its new body. Read More
The Nicoya peninsula in northwestern Costa Rica is one of the most beautiful places on the planet. This 75-mile sliver of land, just south of the Nicaraguan border, is covered with cattle pastures and tropical rain forests that stretch down to the crashing waves of the Pacific Ocean. The coastline is dotted with enclaves of expats who fill their time surfing, learning yoga and meditating on the beach.
For the locals, life is not so idyllic. They live in small, rural villages with limited access to basics such as electricity, linked by rough tracks that are dusty in the dry season and often impassable when it rains. The men earn a living by fishing and farming, or work as laborers or sabaneros (cowboys on huge cattle ranches), while the women cook on wood-burning stoves. Yet Nicoyans have a surprising claim to fame that is attracting the attention of scientists from around the world.
Their secret was uncovered in 2005 by Luis Rosero-Bixby, a demographer at the University of Costa Rica in San José. He used electoral records to work out how long Costa Ricans were living, and found that their life expectancy is surprisingly high. In general, people live longest in the world’s richest countries, where they have the most comfortable lives, the best health care and the lowest risk of infection. But that wasn’t the case here. Read More
The world’s most powerful gene-editing tool, CRISPR-Cas9, gives humans the ability to swap out sections of the genome with less money and time than ever before. That’s a lot of power, and with great power comes great responsibility.
But right now, most of the world doesn’t have regulations about what scientists — and someday, hobbyists — can and can’t do to the double helix. In China, scientists have used CRISPR-Cas9 to modify human embryos. And that has left the rest of the world a little nervous. Read More