Spotting the zebras – strategies for patient finding in rare disease

Treatment for rare diseases – 40 years of innovation

Rare diseases are a group of indications with diverse symptoms and underlying etiologies, which have in common the very feature that names them – their rareness. For a long time, the rarity of such diseases impeded their diagnosis and treatment. Yet the awareness for rare diseases, which in bulk affect some 300 million people worldwide has increased the effort of the medical community and pharmaceutical industries to bring treatments to rare disease patients. Legislative initiatives, such as the 1983 US Orphan Drug Act and 1999 EU Orphan Regulation provide regulatory and economic incentives to drug developers. Together, those initiatives have sparked great progress in the rare disease field catapulting the number of annually FDA approved drugs with an orphan designation drugs from 2 in1983 to 33 in 2020. Notably, those include a comparably high percentage of novel drug modalities, such as gene and cell therapies, highlighting biotech’s willingness to innovate towards curative therapies.

Needle in the haystack – why finding rare disease patients is a challenge

While the general assumption might be that the unmet need of a rare disease will drive the demand for a novel therapeutic, the reality can often look (very) different.

A few rare diseases come with a clear set of symptoms and biomarkers and genetic screening tests. Other rare diseases, despite having a debilitating effect on a person’s quality of life and even life expectancy, can go unnoticed for a long time. Physicians often struggle to piece together the complex set of signs and symptoms into the complete picture of a rare disease. Instead, they offer symptomatic treatments, for example for pain and inflammation that are key symptoms of many rare diseases.

Indeed, while the average diagnosis time in the rare disease field has been estimated to be 4 years, many patients undergo a diagnostic odyssey that takes much longer and puts significant strain on their physical and mental well-being. Next to addressing their disease symptoms, getting the right diagnosis and treatment for their disease can be empowering to patients, making them feel valued and heard, especially if they spent years chasing a diagnosis and a treatment.

Finding rare disease patients – 7 crucial steps

For a drug developing company that brings a novel drug for a rare disease to market, finding the patients who could benefit is key. But how can the drug developer help to cut short the years diagnostic odyssey and fast forward to a treatment for the patient’s rare disease?

For biotechs who don’t have time (and funds), to call any GP in a country to find their patients, we here outline 7 crucial steps for increasing the success of patient finding in the rare disease field.

1.       Clearly describe the set of defining symptoms: Highlight a tell-tale symptom or a unique combination of symptoms that are typical manifestations can help to guide physician interviews productively.

2.       Define the physician target group: Mapping key points in the patient journey allows to find the right type of specialized physicians who treat specific disease manifestations and will help identify the target patients.

3.       Scope the landscape of specialized clinics: Many undiagnosed patients will be referred to specialized clinics at some point in their journey to address organ-specific symptoms or overall immune phenotypes. Clearly scoping all relevant stakeholders at such clinics and raising their awareness for the rare disease in question will help to find patients currently undergoing treatment at such specialized centers.

4.       Define the underlying genotype and advocate for the genetic screening: If the underlying genotype(s) is / are known advocating to include the mutations into screening panels at relevant screening centers can be key in finding patients and increasing diagnostic rates.

5.       Empower patients through disease awareness: Many patients suffering from rare diseases and their caretakers are actively seeking the source of their disease symptoms and try to find a (curative) treatment. Understanding the needs of the patients as primary stakeholders can help raise awareness, for example through social media campaigns or educational measures such as podcasts, in order to make patients (or their caretakers for pediatric patients) aware of the rare disease that might be the cause of the symptoms they experience.

6.       Collaborate with patient advocacy groups: Patient advocacy groups are the extended arm of the patient and can help to bridge the gap between drug makers, physicians, patients and other stakeholders, such as special publications in the field. Collaborating with patient organizations can help to multiply disease awareness through various channels.

7.       Employ novel technology: Artificial intelligence (AI) seems like an overabundant buzzword but can be actually helpful in any area in which large amounts of data need to be structured and analyzed. A number of initiatives are now employing AI to patient finding in rare disease and will likely flourish in the years to come.

Successful patient finding in the rare disease area is a win-win for drug makers and patients. Employing the right strategies and finding the right partners is key in maximizing the chances of success for finding your patients and allowing them to benefit from innovative treatments.

If you would be interested in learning more about our services around patient-finding strategies in rare disease, contact the Healthonauts.

References

1.       https://www.rarediseasesinternational.org/new-scientific-paper-confirms-300-million-people-living-with-a-rare-disease-worldwide/

2.       https://www.nature.com/articles/s41598-024-53554-7

3.       https://www.nature.com/articles/s41573-019-0049-9

4.       https://ojrd.biomedcentral.com/articles/10.1186/s13023-021-01901-6

The Bio Revolution – where science meets science fiction

What do we need to do to avoid the apocalypse, the extinction of our species, a planet without any humans?

Yes, I’m still talking about science. About real, hard bioscience. The science of the biorevolution. Even though many of the technologies of the biorevolution sound like science fiction: gene editing, artificial intelligence, synthetic biology.

Scientists employ these technologies to make human life longer and healthier, and to shape nature into a more human-friendly environment.

We are at the center of this revolution, trying to bend the rules of biology to our will.

The rules that govern biological systems form the very essence of our existence; they are the rules by which we live and die. Humanity stands as the pioneering species that consciously defies these rules, transcending the grip of our biological imperatives like natural selection and Darwinian evolution.

Our journey on this path commenced thousands of years ago when we began to domesticate, or some might say, allowed ourselves to become domesticated by the plants and animals surrounding us, marking the start of our long-term symbiotic relationship with wheats and wolves and cattle, a relationship that altered our destinies as much as that of the planet.

The biotechnological advances of the late 20th and early 21st centuries—genetic screening, gene editing, neuroprosthetics—have catapulted this transition from a horse-drawn carriage to a rocket's pace. These technologies, in their pursuit of altering the course of evolution, fundamentally stretch the boundaries that have defined life on this planet for eons. Scientists now craft entirely new biological entities—organisms that live by their unique rules, propagate, evolve, and proliferate, heedless of the artificial boundaries and policies set by humans.

The biorevolution has become too fast and too complex for regulators and politicians to understand and too powerful for scientists to self-regulate.

Will the biorevolutions and its technologies lead us into a utopia in which physical and mental suffering, hunger, disease, and even aging and death become things of the past? Or are the changes we're making to human biology the first step toward our downfall as a species? Will they usher in an age of modern-day eugenics, exacerbating social inequality and erasing biodiversity?

While humans aren't great at foreseeing the consequences of their long-term actions, they excel at envisioning future doom scenarios—ranging from genetically selected superhumans in "Gattaca" to genetically-modified humans in "X-Men" to the myriad different versions of the zombie apocalypse.

Understanding where modern bioscience is headed is important to everyone because it will affect everyone. Viral diseases and bioweapons, methods for genetic selection and genetic upgrades, artificial intelligence algorithms, and neuroprosthetics will affect everyone. They will affect our understanding of humanity and our destiny as a species.

To avoid the apocalypse, the extinction of our species, a planet without any humans, we need to understand those technologies, need to apply them with care and try to consider the long term consequences of our actions.

Rewriting humanity

When it comes to scientific discovery, there’s big news and there’s small news.

Lately, we’ve been drowning in the big COVID news: numbers, vaccines, mutants, and so on, leaving us just enough air to swim to the surface here and there to absorb the most recent success or failure of our favorite soccer team.

Still, there are science news important enough to penetrate the COVID bubble in our brains.

One such piece of news is Intellia’s first ever in vivo gene editing in humans - a milestone for a technology that can literally change humanity’s source code.

A permanent change

The US biotech Intellia was cofounded by Jennifer Doudna, one of a number of scientists who discovered the functionality of the bacterial CRISPR/CAS9 system through multiple discovery and one of two leading CRISPR scientists who were awarded the Noble Prize in 2020.

Gene therapy (the introduction of foreign genetic material into humans to cure disease) has been tested in patients for three decades though it was only in the 2010s that a few gene therapies saw approvals by the European and US regulatory agencies. CRISPR/CAS9 comes with a new level of precision that classical gene therapies don’t have. It allows making a change at a specific location in the genome, working with the cellular DNA repair machinery to excise and reknit DNA. With such a tool we can alter, remove or repair genes. If successful, CRISPR/CAS9 therapy could become a one-shot cure for many genetic diseases. It could also be a means to alter the human germline to select for desirable traits, like height, eye color, intelligence, or resistance against certain diseases. The latter was infamously attempted by Chinese researcher He Jiankui, now sentenced to three years in prison for trying to make human babies resistant to HIV...

While a number of researchers in biotechs and universities had used CRISPR-based gene therapy in patients, they performed the editing outside the body - a so-called ex vivo approach. Here, cells are extracted from the patient, genetically modified in the lab and then the altered cells are put back into the patient. Needless to say, ex vivo therapies are difficult, time consuming, prone to variability, and, most importantly – only work for diseases where it is possible to remove and add back cells into the patient. This is mainly true for blood diseases, such as Sickle cell anemia.

Intellia now performed a so-called in vivo approach, changing the gene directly in the patient. To be precise, they removed the gene which codes for the transthyretin protein, from the liver cells of patients, suffering from ATTR amyloidosis. This rare and fatal disease is caused by a mutation that causes buildups of misfolded transthyretin protein in the organs of the human body. A month after a single injection with Intellia’s CRISPR therapy, the researchers saw a decrease in protein levels of 80-96% in three patients.

On our way to Gattaca?

With CRISPR/CAS9 at our hands, will we soon be able to cure all genetic diseases including cancer? And if the method is so straightforward, how close are we to ordering our CRISPR kits for home use on Amazon and start improving our genomes, to turn ourselves in Gattaca-style beautiful and intelligent people?

Both scenarios are further away than it might appear at first glance, and not just because of ethical constraints. Changing the genome is not as easy as it sounds. While the technology appears ready (at least as ready as it gets, considering that it was discovered a mere decade ago), other factors challenge the use of CRISPR/ CAS9 just as much as classical gene therapies:

1.       We don’t understand the human genome well enough to make the changes we want.

2.       We don’t get the CRISPR/ CAS9 therapy (or any other gene therapy) where it needs to act.

Our lack of understanding is one of the major reasons of why, with all our fancy technology we in some respects haven’t moved a lot, have not cured cancer or Alzheimer’s or a myriad of other diseases. While we have some idea of deregulated genes in those diseases, we don’t fully understand how the disease manifestations are produced through the interplay of genes, epigenetics, and lifestyle factors. Trying to alter complex genetic networks will yield no result in the best case, and unintended consequences in worst.

There are diseases, however, where the removal of a single malfunctional gene, might be enough to halt their progression and potentially cure them. This is the case for numerous monogenic diseases, like the one that Intellia tackled - ATTR amyloidosis.

But even in cases, where the culprit gene is clear and we know where to put the DNA scalpel, we still need to be able to access the gene. Doing this is easier in a petri dish (as done in the ex vivo approaches for modifying blood cells or when manipulating human germ cells) than inside a human being. To be effective, enough of the gene therapy needs to reach the diseased tissue before the therapy is being diluted, neutralized or excreted. The human body is designed to get rid of foreign agents and not to neatly deliver them to the spot where the researcher wants them to act. Notably, one of the body’s major detoxifying organs is the liver, and most unwanted agents, be it an excess of alcohol, drugs or a gene therapies, will find their way there. For true in vivo approaches (meaning a therapy that is delivered systemically rather than locally, for example by direct injection into the eye), the liver is likely the easiest tissue to reach.

High stakes and low-hanging fruits

Researchers call those, comparably easy applications, the low-hanging fruit. While the groundbreaking example of Intellia would qualify as such as low-hanging fruit, it is an important proof of the technology, nonetheless. Does this mean it will work for more complex applications, such as multigenic diseases or difficult to reach tissues?

We don’t know yet.

But in science, problems are there to be solved and often serendipity is the scientist’s best friend. When Doudna and her peers were researching the bacterial immune system components, they hadn’t planned to hand humanity a tool that can rewrite its source code. During decades of hard work, they stumbled upon this particular application, and they were smart enough to understand what it could do and to contextualize its consequences.

Chances are, scientists will overcome the hurdles that CRISR is facing in more complex applications too. Maybe intentionally and maybe accidently, and probably through a combination of both. How soon, we can only guess.

But one thing is clear, we must acknowledge CRISPR/CAS9’s full potential with all its good and bad implications for humankind and prepare for the ethical challenges that it will bring.

A way out of the risk-benefit labyrinth

In the past week, many European countries halted vaccinations with AstraZeneca’s COVID-19 vaccine after rare cases of thromboses.  

How do we weigh the risk for the individual who is being vaccinated against the societal risk of the pandemic and its by-products?  

Individual risk perception – where hunches trump numbers  

If we want to do more than just sit at home and wait for it all to end, we must accept a certain level of danger in our lives. We define our comfort zones, deciding how risky our professions, free time activities and lifestyles can be.

When making those decisions, individual perception of risk often differs significantly from the actual probability of the risky event occurring.

On the one hand, our brains bias us positively towards occupations that are fun and/ or addictive. For activities that bring (short-term) pleasure, like sun-bathing, drinking, smoking, reckless driving, unhealthy eating, and frying our brains with hours of social media doom scrolling – we are much more willing to accept the risk of short or long-term negative effects.

On the other hand, human brains don’t seem to be made for understanding probabilities in more than a metaphysical way. If they were, no one would EVER play the lottery.

But there is always the hope to be THE ONE. And in that sense, our brains can actually process the logic of probabilities. Because being the one to crack the jackpot isn’t impossible, it’s just extremely unlikely.  

It works the same way for bad events. The fear of flying appears unreasonable, when comparing the actual risk of a plane crash to the risk of being in a car, with the much more real danger of fatal accidents.

Assessing risk-benefit for medications – numbers and psychology

Most people take some kind of medication for treating acute symptoms such as headaches, chronic conditions such as high blood pressure, or in the worst case, life-threatening diseases such as cancer.

What is an acceptable risk profile for a drug?

Depends on its benefit.

Medical agencies such as the American FDA or the European EMA weigh the good a medication does for patients against the potential harm it might cause before allowing it onto the market. The acceptable risk of side-effects should obviously be much higher for a drug that treats a fatal disease than for one that treats something minor like a headache.

While this logic of risk vs. benefit makes sense on paper, human psychology seems to deviate. For example, many people would be willing to accept quite severe side-effects for weight loss medication or acne treatments. The severity of a condition, and perceived benefit of a treatment are different for everyone, and determine the risk threshold.

The invisible danger – assessing risks of preventative measures

Our risk threshold is much lower when it comes to preventative treatments, medications, or vaccines we take to avoid getting sick. Here, we always have to weigh the immediate risk (potential side-effect of the preventative treatment) against the risk of getting ill (maybe) in some unknown future.

The risk of contracting COVID-19 is difficult to assess and can be calculated based on where we live, how many people we meet, where we meet them and so on. For example, for my location the probability that any person, I meet has COVID-19 is currently 3%, with the risk of catching the disease depending on the type of interaction (inside vs. outside, long vs. short, close vs. distant, quiet vs. loud singing etc.).

The risk of serious complications or even death differs significantly between age groups. While in the overall population in Germany 3%, of people who got COVID-19 have died with the disease, this percentage is up to a 100-fold lower in younger patients.

The AstraZeneca vaccine has had bad press since its bumpy start. After the initially published efficacy was lower than that of the contestants from BioNTech/ Pfizer and Moderna, and the way the study was done and data published felt (honestly) a bit messy, with muddled-up dosing regimens, unpublished cohorts and not enough elderly patients in the initial study to draw conclusions for those high-risk patients. While the efficacy is currently estimated at slightly above 60%, the vaccine offers a reassuring 100% protection against severe disease, hospitalization and death.

But the recent discussion isn’t so much about the efficacy of the vaccine than about potential safety concerns, namely blood clots (thrombotic events). The general thrombosis risk is LOWER than in the general population, and for pulmonary embolism definitely lower than in COVID-19 patients.

But with the AstraZeneca vaccine, there might be a higher risk of specific brain thromboses - cerebrovascular venous and sinus thrombosis. That said, those thrombosis occurred in 25 out of 20 million vaccinated people in Europe – a chance of slightly higher than one in a million, and the causal link between the vaccine and the thrombosis is not (yet?) established. On the 18th of March, the EMA clearly stated that the benefits of the AstraZeneca vaccine outweigh the risks of those rare events.

That recommendation notwithstanding, each person is allowed to decide on the risk they are willing to take for themselves. In our society, individual risk trumps society risk.

BUT, if we choose against vaccination, which is and should be anyone’s right, we influence not only ourselves. We make it easier for the virus to spread. The higher the numbers, the higher the chance for ourselves and others to contract the diseases, to die from it or to develop long term disability. And the harm the pandemic causes goes beyond the direct effects of COVID-19. Measures, such as lockdowns and school closure are a severe burden for mental health, with depression rates in adults doubled in comparison to pre-Pandemic levels.

Risk tradeoffs are never easy, not for the individual and not for society as a whole. I am glad to live in a society that respects my own, often irrational perception of risk, that allows me to get sunburns, and hangovers, and spend thousands on lottery tickets that never win…

But when it comes to vaccination, I feel that the individual and societal risks are basically aligned – the sooner the pandemic is over, the better it will be for everyone.

If you ask me – I would take a shot of AstraZeneca (or any of the other vaccines) in a heartbeat as soon as anyone offers. In the meantime, I’m patiently waiting with my sleeve rolled up.

An ally for curing our incomprehensible organ

With this post, the psychedelic journey of my blog comes to an end – at least for now. After discussing the troubled history and the molecular level effects of LSD and other psychedelics, let’s take one last plunge into the mystical sea of colors. In today’s post I will try (and largely fail, sorry for the spoiler) to understand how psychedelics impact a person’s feeling of self, and how this might help patients with psychiatric disorders.

A personal note to begin with

Diving into the area of brain research usually leaves me with the feeling that I know nothing at all. Once this feeling strikes me, I start wondering if it isn’t an inherently flawed endeavor, for humans to try comprehending their own brains. My cowardice when it comes to brain research was sealed before I turned twenty-one, when I abandoned my idea of becoming a neurobiologist and instead ventured into molecular biology. Studying the brain just seemed too daunting.

To the current day, while researchers gather more and more information, the big questions about the brain, about humanity seem to elude us. Could psychedelics be an ally on our quest to try to understand the brain? Indeed, the word psychedelic, which comes from Greek, means something like ‘mind manifesting’, highlighting the drug’s ability to bring hidden aspects of the mind out of stealth mode and to the forefront of our consciousness.

What do psychedelics do to the higher command center?

In my last post, I introduced the brain as a midsize company, and discussed its molecular interactions, represented as the level of single employees, and different brain areas represented as individual departments. Now we reach the higher command center – the executive level of our brain company that produces our feeling of self. The neural correlates of this self, however, are incompletely understood. It’s like a magic trick that the lump of cells residing in our skulls plays, turning chemical and electrical signals into a feeling of unity comprising all the parallel processes that happen in our brains.

This sense of self-unity can be blurred or even dissolved by LSD and other psychedelics, also described as a mystical-type experience. While this doesn’t necessarily mean that we can extrapolate one-to-one to normal (whatever that means) states of consciousness – psychedelics might allow us to draw some conclusions on how self is created, and how it is disturbed in psychiatric disorders.

But how can we study the disturbance of a process we don’t fully understand?

The fallback method of modern brain science are imaging studies, which highlight areas of activity in the brain. Yet, a number of recent brain imaging studies have yielded diverging results for brain activity during states of self dissolution. Maybe this inconsistency is due to differences in the study setup, but likely there is also the component of individual differences in the creation of self and its dissolution. It seems that there isn’t a one-size fits all explanation – at least not yet.

Nevertheless, even though we don’t understand what exactly is happening during those mystical states, a positively perceived ego dissolution seems to corelate with success of psychedelic-aided therapy for addiction, depression, and other psychiatric diseases.

Something that happens during those few hours of loss of self leaves a lasting imprint on patient’s brains.

One hypothesis brings us back to the reset idea – think switching off and on a computer. Now I admit that I am speculating, but maybe the temporary loss of self could lead to a shortcut in the negative or obsessive thought patterns, which are etched into the brains of patients with depression, addiction, and other diseases - like a break in an electronic circuit in the unplugged computer. When switching the self back on, negative patterns are not reinstated to the same extent and could be fully overcome.

Beyond self

Even our complex brain company does not exist in a vacuum and is only a small part of a big machine that is interconnected with many other entities. There isn’t a lot of business you can do all by your lonesome.

Similar to our company, our feeling of self, created by our brain does not exist is not in a vacuum and depends on interactions with and reactions by others. In many psychiatric diseases, so-called social cognition, thoughts, and emotions that integrate self with others, is altered. This can lead to social withdrawal – which in many cases enhances the pathology in a downwards spiral.

Interestingly, a number of studies report that psychedelics could have a positive effect on the interaction with others. For example, LSD and psilocybin have been shown to increase emotional empathy and reduce feelings of social exclusion. Together those effects might reduce social withdrawal and improve interactions, with long-term benefits for patients. Although there is currently only thin data on the long-term interpersonal effects that psychedelics have in psychiatric patients, a few studies highlighted self-reported improvements in pro-social behavior, which was beneficial for overcoming smoking addiction and for depression.

A way to cure patients with psychiatric diseases

Treating psychiatric patients with drugs that are perceived as so-called “hard” drugs, which induce hallucinations, and which can have severe mental (if not necessarily physical) side-effects is prone to create a public headshake if not a fully-fledged public outcry. I must admit that I myself was extremely skeptical about the idea before diving deeper into the topic.

However, hallucinogenic, ego-dissolving substances still appear benign when contrasted against methods that have been used for treating mentally ill patients in the past. Indeed, the discovery that LSD changes the chemistry of the brain preceded the first approved depression drug (the monoamine oxidase inhibitor Iproniazid)  by some years and might have been instrumental in paving the way for medical intervention for depression. Before the discovery that chemical substances could treat psychological ailments, there was either psychotherapy or sedation, not to forget the host of medieval methods –electroshock therapy, insulin coma, and of course the lobotomy. In this last, Nobel-prizing winning technology the prefrontal lobes of the brain were surgically removed, first by scalpel and later, as popularized in the United states by Walter Freeman, by icepick. Mark you, the prime age of the icepick brain surgery was the 1950s and not some long-gone times. In comparison, the discovery of drugs which alter brain chemistry, even if the compound might make you see some colors, seem like a massive leap.

Indeed, a number of recent studies showed that patients with alcohol and nicotine addiction, as well as terminal cancer patients suffering from anxiety and depression, individuals with treatment resistant depression and post-traumatic stress disorder benefited from psychedelic treatment. Compared to currently used, psychedelics might have some major advantages – fast onset of improvement (which imaginably is of high relevance for patients with acute suicidal ideas), long duration (meaning patients wouldn’t have to take medication constantly), fewer severe side-effects and low addictive potential.

LSD and other psychedelics appear especially suited for inward-looking psychiatric diseases, characterized by ruminating thought patterns, such as depression and anxiety, addiction, and OCD. In contrast, for other diseases, such as schizophrenia, they are likely to cause harm, instead. Importantly for treating depression, psychedelics also appear to change emotions, and in a controlled setting reduce the response to negative stimuli.

While those results are encouraging, caution is warranted, because there are several sources of bias:

A)      Except for very few studies, those tests of psychedelics were uncontrolled meaning, the patients knew they were going to be treated with the drug. Even expecting to get better will make you better, an effect which is especially evident for psychiatric diseases.

B)      In the case of psychedelics, it is difficult to find the right control conditions. A placebo – a compound that does nothing – is not a good comparison for a compound expected to cause hallucinations, meaning a substance that has an effect akin to that of psychedelics is required.

C)      It is difficult to disentangle the effects of the accompanying therapy from the effects of the drug itself. From a patient perspective, this doesn’t matter much, as long as the therapy works. From the researcher’s perspective, however, it makes it difficult to understand the true contribution of the psychedelic. There are reports of psychiatric patients, who benefited from psycholytic therapy (low dose psychedelic + talk therapy), but also those who got better with psychedelic therapy (high dose psychedelic without additional psychotherapy). All modern studies, however, give psychedelics in the context of psychotherapy, which might be important for the proper integration of the experience and subsequent treatment success.

D)      The confirmation bias of researchers and patients contributing to psychedelics trials is likely especially high, given the ostracized status of the field – those who spent their time and energy on psychedelics research will want it to work very badly and patients who are willing to undergo this treatment will likely have a strong belief that they will benefit.

The research field of psychedelics, despite its decade long history, seems at the beginning of a new era, with more controlled studies, allowing researchers to gauge the true benefits for psychiatric patients.  

And maybe, on the long run, the consciousness-altering, ego-dissolving nature of psychedelics could help use curing the organ we can’t quite understand.

Benevolent anarchy in the brain

Let’s take up, where we left off in the last post in which I discussed, Albert Hoffman’s discovery: the psychedelic drug LSD and its decades-long roller coaster ride, from high hopes for using it as a drug to treat psychiatric patients in the 1950s and 60s, over the flood of psychedelic enlightenment seekers in Hippie era, to its misappropriation for the CIA’s notorious MK-Ultra program, and finally its second spring as an experimental psychiatric drug.

After seven decades of LSD use, a huge pile of biomedical data accumulated, measuring what happens in the human brain under influence of psychedelics.

Enough to make sense of the psychedelic experience?

Brain company Inc

To appreciate the potential of the psychedelic drugs, we must take a step back and try to understand how they modify our brains. But in order to comprehend this, we need to take another step back and take a deeper look at the functional architecture of the brain.

When trying to explain the workings of the brain, I’m going to use the metaphor of a midsize company - let’s see how well this will play out.

On the highest level, we have the company itself, which is perceived as a single entity by outside observers, as well as by its own, individual units. In the brain this translates into macrolevel consciousness or feeling of self. 

One level lower, we have the individual divisions that deal with separate functions, like accounting, sales and so on. In the brain, those macrostructures are the areas that are assigned to different functionalities, such as speech. Their work isn’t entirely separate, often multiple areas partake in the same function. If one of those areas is damaged and drops off - like if everyone from accounting went out for lunch, had a bad burrito and none of them shows up for work the next day - one of the other departments, like the folks from marketing, can take over, though it might take them some time to learn the ropes. The same kind of functional take-over can happen in the brains of patients with brain areas that are damaged (for example after a stroke or head trauma) or underused (for example for patients losing a primary sense – such as vision)– a phenomenon called rewiring or neuroplasticity.

A further step down, we reach the molecular level, let’s say the company’s individual employees and their interactions. In the brain those are the signaling molecules (neurotransmitters) and the receptors they bind. Changes on this molecular level can backfire to the whole apparatus if they are magnified – think a single colleague is writing an email disclosing personal secrets of the boss to another person and soon everyone in the company knows all about it.

Small changes with big impact – the molecular level

We’ll start the psychedelic journey through the brain by zooming into the molecular level - the level of direct interaction between the psychedelic molecule and an individual unit of the brain architecture, a receptor.

LSD and other psychedelics bind different receptors in the brain, but one of them stands out from the crowd: the Serotonin-2-A receptor.

What does this Serotonin-2-A receptor do? Serotonin is an ancient molecule (already present in singe cell organisms), with diverse roles in and outside the brain. It is a neurotransmitter from the monoamine group, which are master modulators of the brain’s communication systems – one could say, they are in charge of the company’s mailing lists. Those neurotransmitters are involved in virtually all brain functions. Unsurprisingly if there is too much or too little of them, complications arise in the brain and can lead to psychiatric disorders, just like too much or too little, or too untargeted communication might hurt the organization of our company.

Lack of brain serotonin is linked to depression and anxiety. The major class of antidepressants, so-called selective serotonin reuptake inhibitors, such as Prozac function by raising levels of serotonin in the brain. Deregulation of the serotonergic system has also been linked to schizophrenia, and indeed, LSD was considered a means of inducing an artificial psychosis in the early days of its use, though its effect seems to capture only certain aspects of the disease.

Binding to the Serotonin-2-A receptor appears crucial for the psychedelic impact on the brain, a fact strengthened by the observation that an antagonist the Serotonin-2-A receptor (a drug that does the opposite of LSD), a molecule called ketanserin, abolishes all subjective psychedelic effects in humans on LSD.  Those effects include visual changes such as hallucinations or distortions but also changes in thoughts and emotions, up to the loss of self feeling.

Interestingly, the effects that psychedelics have on individual brain cells might be more than a short-term occurrence. Different studies have shown that psychedelics cause lasting changes in cortical neurons of mice – so-called neuroplasticity that we discussed earlier (like if the marketing department permanently took over some of the accounting functions). In the case of a psychedelics experience that doesn’t mean that the acute effects lasts longer than the actual trip, though it might mean that the transformations that are made during the trip – good or bad – can be permanently etched into the brain. It remains to be seen if this phenomenon seen in mice translates into humans, but it could be an explanation for sometimes described psychedelic ‘miracle cures’ for OCD or alcoholism.

Trying to grasp the bigger picture – the macro level

There are a number of newer brain imaging and connectivity studies that give hints to which areas and networks in the brain are altered by psychedelic influence. The results of those studies, however, often contradict one another and none of the current working models is supported by all available evidence. Of course, variations in dose and type of psychedelic used, as well as other parameter such as the exact brain imaging methods, and the type of study subjects (healthy volunteers or psychiatric patients) account for at least some of the incongruity.

One common observation is that psychedelics make the brain more anarchical – they increase its entropy. In our company one could imagine a breakdown of the rigid structures into different division and everyone in the company just does whatever they feel like that day.

There are different hypotheses for how this state of messiness arises in the brain, which don’t necessarily contradict one another.

One idea is that the filtering of input that reaches the higher command center, the prefrontal cortex by a structure called the thalamus is reduced. Subsequently, there is less top-down and more bottom-up processing, meaning there is a higher level of sensory input in the prefrontal cortex, which leads to increased blood flow and could finally be responsible for sensory changes, changed cognition and ego dissolution. While it was originally thought that this causes a completely untargeted bombardment with sensory stimuli, there are newer studies that show that there seems to be a certain level of targeting, for which areas in the cortex receive more information. On the example of our company this would mean that only certain, instead of all departments get the spam filter removed from their email programs.

Another working model that is supported by some of the current studies is that LSD and other psychedelics reduce the activity or connectivity of the so-called default mode network. The default mode network is a large-scale brain network involved in introspective thinking, including negative patterns such as self-criticism and ruminating thoughts, which is thought to be overactive in depression and anxiety.

Overall, psychedelic-induced disordering or reordering of the brain could unhinge negative patterns, be it by changes in filtering, changes in blood supply or rewiring.

I would imagine the effect in a way that is similar to rebooting a computer, a proven solution that has solved many of my IT issues.  

Let’s continue next time with one last post on psychedelics and try to shed light on the question how those molecular and macrolevel changes reflect to the management level, the feeling of self that seems to be so drastically altered during and sometimes after the psychedelic experience and how this might translate into treatments for psychiatric patients.

The biochemistry of the mystical - of magical bike rides, dolphin linguists and hopes for depression patients

Our brain is our context tool, the biochemical and electrical machine that makes sense of our surroundings and integrates our behavior with that of other members of our species, mingling our past and current experiences into a state of being that we perceive as consciousness, as self.

The feeling of self includes the constant flow of sensorial inputs, which are run through our brains’ relevance filters and integrated with a stream of thoughts and emotions. Sometimes this stream transports happy feelings. Too often though, nagging worries drift along, and can accelerate into the unruly currents of anxiety and depression.

Some people have experienced a state that goes beyond the feeling of self – a so-called mystical experience of boundless and oneness, which can occur in nature, through meditation or religious ritual.

As spiritual as those mystical states might feel to the individual, they are – naturally - part of the brain biochemistry too.

The intersection of the feeling of self and the perceived mystical self-loss-experience is exemplified by the action of Lysergic acid diethylamide (LSD) and other psychedelic drugs.

“When you study natural science and the miracles of creation, if you don't turn into a mystic you are not a natural scientist.” Albert Hofmann once said.

The Suisse chemist worked at Sandoz Laboratories (now Novartis), where he synthesized a substance called LSD in 1938. Finding no immediate use for his discovery he let it rest for a couple of years before revisiting it in 1943, after he’d experienced a “peculiar presentiment”.

The ball began rolling, when he accidently ingested a bit of the substance, which led to what he described as a “not unpleasant intoxicated-like condition, characterized by an extremely stimulated imagination”.

Intrigued he consumed what he considered the smallest active (in reality quite decent dose) of 250 micrograms of LSD. What followed was a memorable bicycle trip that Hofmann took from the lab to his home. While at first, he was terrified and paranoid those feelings gave way to enjoyment of what he was experiencing. “Little by little I could begin to enjoy the unprecedented colors and plays of shapes that persisted behind my closed eyes.”

On that day, Hofmann discovered LSD was a psychedelic substance. It changed him forever.

He would later say:

“LSD is just a tool to turn us into what we’re supposed to be.”

He wasn’t the first to see this potential in psychedelics - for centuries, different native cultures had used substances such as “magic” mushrooms, mescaline or ayahuasca as tools in religious rituals, to enhance spirituality.

Invigorated by his bicycle-trip, Hofmann hoped that his new discovery would find uses for treatment of psychiatric patients. The idea was picked up quickly and a number of psychiatrists investigated the effects of LSD in psychiatric patients, many reporting benefits, but few living up to scientific standards that would make the results interpretable today.

While LSD flooded the Hippie movement and broadened (or at least altered) the consciousness of the flower-power generation, the drug didn’t find the accepted medical use as Hofmann had hoped for.

Meanwhile, the supposed transformative qualities of LSD spawned new lines of experimentation which contributed to the drug’s notoriety. From slipping LSD to ignorant subjects in the CIA’s MK Ultra program (which was supposed to defend against communistic mind-control techniques), to  NASA-founded experiment of interspecies (as preparation for extraterrestrial) communication. In the latter John Lilly (himself a fond LSD user) tried to communicate with dolphins and injected LSD into the animals – which luckily didn’t do any harm to them but also didn’t make them speak English. There is some more beef to the dolphin story that goes from absurd to sad, but that’s for another time…

When the summer of love came to an end, the idea that psychedelics where a means to cure mental illness and gain a higher state of reality, be it in psychotherapy or in a recreational setting, was dwindling. As another Hof(f)man(n) said - this time part time revolutionary Abbie Hoffman:

“The 60’s are gone, dope will never be as cheap, sex never as free, and the rock and roll never as great.”

At the end of the 1960s, the Drug Enforcement Administration classified LSD a controlled substance. Other psychedelics followed the same fate. Hofmann’s miracle drug had turned into his “problem child.”

Psychedelics lurked in the shadows for decades, not bothering many people except for recreational users and a few dedicated scientists, artists and drug policy reformers who hadn’t quite given up on the idea that psychedelics could hold benefit for humankind.

In recent years though, the concept of using psychedelics for treating patients with mental illness is slowly rejuvenated and starts reaching the mainstream media. A few reports showed that psychoactive and psychedelic drugs helped patients with depression, post-traumatic stress disorder and other psychiatric diseases when combined with talk therapy. Those studies go beyond the mountain of anecdotal evidence accumulated in the 1950s and 60s.

Does this mean we should all take LSD and we will live happily ever after? Likely not. There appear to be severe psychological risks to psychedelics and a bad trip might be just as transformative (in a negative way) as a good one. But maybe there is a chance to exploit the substances in a controlled setting for treatment of psychiatric diseases, and – who knows – for personal enlightenment.

First, though, we will have to gain a better understanding what LSD and other psychedelics do to the brain.

Tune in next Thursday for a discussion of recent results of bioimaging and behavioral studies, which try to decipher the complex action of psychedelics on the neurobiology of our brains.

Until then I leave you with another saying from Albert Hoffman, who died in 2008, witnessing only the beginnings of the recent upsurge in psychedelics research:

“I go back to where I came from, to where I was before I was born, that’s all.”

The unpopular solution – vaccine hopes, fears and denials

Within the last week we’ve experienced a sprint of good news – with press releases showing vaccine efficacy above 90% toppling over one another as BioNTech/Pfizer and Moderna race their vaccines towards the finish line.

The efficacy found in those trials is spectacularly higher than the set approval target of 50% from the United States Food and Drug Administration and much higher than effectiveness of vaccines against seasonal flu, which need to be “remade” each year, due to the influenza virus’ high mutation rate.

Under normal circumstances  - meaning “old normal” - vaccine development takes more than 10 years even in a best case scenario. The companies that are now submitting their data to regulators did it in less than a year.

There may be differences in safety, temperature stability and associations to Dolly Parton (the latter being a decisive factor for my own humble favoritism). But contrary to the usual drug to market contest, where the first drug over the finish line gains a (sometime massive) advantage, this vaccine race knows only winners. The demands for COVID-19 vaccine are so high that there is space for many contestants to take the crown.

How does the public react to that hopeful piece of news?

For people like me, the news of a potentially effective and safe vaccine mean a relief that equals a huge suffocating weight (huge, like for example the sum of all pandemic weight gain in my city of 4 million people) falling off my chest. An effective vaccine seems to be the ONLY realistic hope of ending the pandemic soon and without even more dramatic casualties and economic damage, than we’re already experiencing.

There is a second group of people, the indifferent bunch, who don’t seem too enthusiastic about the vaccine news, thinking – SO WHAT? They’d seen the development of an effective vaccine as a given and feel nothing but a mild disappointment that the looming vaccine doesn’t end the pandemic in an instant and that it may still take at least a year or more for the existence of vaccines to translate into a return to normal – in this case “old normal” or a better version of “new normal” .

Then there is a third group of people: those who don’t want to be vaccinated. Some of those people have concerns that vaccination might do more harm to one’s health than it would do good. Others see vaccination as the work of the devil, as a big ploy of evil elites, who try enslaving the ignorant population, as a money-making scheme by the pharma industry, who hide vaccines’ dangerous side-effects, from autism to mind control via microchips (I guess I don’t have to spell out that neither autism nor microchip-mind control are side effects of vaccines, o wait, now I’m spelling it out anyways), and that as a final coup, those vaccines will be delivered by genetically modified mosquitoes (which, I must admit might actually work in the future) .

The antivaccination movement hasn’t been born amid the pandemic but as other anti-science movements, is gaining momentum as the pandemic tide washes over us, leaving people confused and desperate for alternative explanations – explanations which deviate from the general tenor of “This sucks but it might be over eventually if we all grit our teeth and push through”.

 

Underlying vaccination hesitancy is a deep-set human refusal to acknowledge bad things might befall us, or our children. It’s too abstract to imagine the threat from diseases, which have been virtually eradicated by vaccination, or in the case of COVID-19, too abstract to connect the pictures on the television of overrun hospitals and of exponential growth curves to our own lives. We feel young, and healthy and above all invincible – even if we never truly are.

And then there is the believe in alternative truths – COVID19 is a hoax and scientists are idiots in league with dark powers... The ability to hold those different theories in one’s mind is a complex feat worthy of Orwell’s doublethink (though it might even be triplethink here): 1) believing in the impotence of science, 2)  granting scientists with the ability to bring about the scientific miracles worthy of a dystopian sci-fi thriller (microchip-mosquito-mind-control) 3) believing that the protection from those high-tech threats lies in methods worthy of a medieval witch craze, like wrapping your head in metallic foil or wearing protective gemstone charms.

While those ideas appear as enjoyably absurd as a Monty Pythons sketch, the spillover of the crazy ideas into mainstream thinking endangers the population and the economy. Polls say that only ~50-65% of people want to be vaccinated against COVID19 in the US, UK, Germany.

SO WHAT? say the indifferent (because that’s what they always say) ...

If those people don’t want to get vaccinated, more vaccine left for the smart ones who’ll get their shot at the shot earlier. BUT (and that one’s a clear all caps) BUT we need enough people vaccinated to achieve herd immunity and hopefully make the virus disappear. And the people who refuse vaccination, and who will likely also refuse other security measures like wearing masks and keeping social distance, will still fall ill with COVID-19, will still need treatment in hospitals and take up space in ICUs. It’s not an option to deny them treatment for their own stupidity. Punishing stupidity is not a tempting idea as all of us are prone to endanger our health with some kind of stupid behavior, from unhealthy lifestyle choices, from fatty food to dangerous sports.

No, punishing stupidity is not and shouldn’t be an option, and yet, we have to live with the reality that the stupidity of some has the power to punish the rest of society with their antivaccination stance.

How to celebrate science in anti-science times

Today is world science day, yesterday the news on a potentially efficacious vaccine against COVID-19 were declared a victory for science.

But the reality that scientists face is much less rosy than those news might suggest. Large parts of the population seem to be suffering from science-fatigue, from the unwillingness to try to comprehend scientific facts.

There are different explanations for how the world works.

Even as a scientist, no let me rephrase this, especially as a scientist, I accept this.

There is a lot of grey between the black and white, there is a question behind every answer.

As scientists we learn something new each single day. We don’t need to defend a dogma if its proven wrong, we accept a better explanation if one comes our way and we proudly proclaim that there is much more we don’t know than we do know about the world.

But science suffers from a perception problem. People believe that science offers hard facts and that science can fix things - preferably quickly and without effort. Laboratories should produce shiny new technologies, cure diseases, and find wonder drugs that allow us to eat as much as we want without gaining weight.

With the Corona Pandemic and the climate crisis we are facing problems that can’t be fixed quickly, problems that are as complex as possible solutions, problems that won’t go away because we chose to ignore them, try as we might.

If we want to halt the spread of disease, if we want to slow the downwards slope towards an inhabitable planet, it won’t be easy, it will require sacrifice. That’s what scientists tell us.

But people don’t want to hear bad news, don’t want to change their lifestyle in even a miniscule way, agitatedly defend their right to just go on like we always did, while the forests are burning, the arctic ice is melting and the pandemic deaths are piling up.

We will all die eventually. That much is true. But should this kind of fatalism drive us towards a selfish

Après moi, le deluge attitude that endangers our fellow humans to die from a deadly virus, that will leave a wrecked earth for the children?

Shouldn’t the threats we’re facing make us open for the voice of reason?

Unfortunately, not.

Climate scientists, epidemiologists and doctors are under attack from populist leaders and media and from an increasingly agitated public, out to (in some cases literally) kill those messengers of bad news.

From Galileo to Darwin, scientists had to suffer the rage of those who saw the status quo threatened.

But scientists who warn about the spread of the pandemic didn’t make up the Corona virus, just as Darwin didn’t invent evolution and Galileo didn’t exchange the sun and the earth, as if hanging a new painting at the center of the universe – the facts were always there, the scientists were just pointing them out.

Now again, scientists and doctors who are warning about the problem, who try to explain its complexity, whose predictions are being proven right over and over suffer the backlash of the anti-science climate, are attacked in the crudest ways and even receive death threats.

The anti-science climate hasn’t started with the pandemic, indeed discussions about a war on science have been waged for years, culminating in disbelief in climate change and in anti-vaccination movements.

But the pandemic intensifies the problem because it brings the debate to the forefront. It makes it harder for scientists to maneuver the new terrain of this unprecedented situation, with a lack of canonical knowledge, while under constant siege by (social) media to produce a solution quickly!

What should scientists do then? Stop preaching scientific facts? Move science back into the ivory tower and keep scientific communication to academic journals and conferences, where no alternative facts outside the scientific realm interfere with the blissful vibes of bar graphs and p-values? Doesn’t appear to be a good idea. While scientists are no politicians and shouldn’t speak out on all topics, they should speaks out on the topics, on which they have the most knowledge and they should advise the public on consequences of actions – and non-actions, even if the consequences are dire.

The pandora’s box problem in science

Earth-shaking discoveries

There are many discoveries in science, which make but a small impact on the world, discoveries that are tiny pieces of the puzzle, adding together to answer the grand scientific questions. 

There is another type of scientific discovery, the one which has the potential to impact the fate of humankind in some profound way.

How does it feel for a researcher to make this kind of discovery?

Is it elating?

Terrifying?

A bit of both?

I wouldn’t be able to tell, anything I discovered in my time as a scientist unfortunately (or maybe fortunately) didn’t have the potential to shake the foundations of humanity (or shake the foundation of anything, except maybe my ego).

But what if your discovery does just that?

Shake the foundations of humanity.

Scientific discovery suffers from a pandora’s box problem. Once a finding has been communicated to other scientists, it is impossible to take it back.

Scientists call to action – or non-action

It tells you something about the impact of a technology if the scientists themselves, those closest to the discovery are the ones to sound the alarm bells. 

In the (in)famous 1939 Einstein–Szilárd letter, written  Leó Szilárd and signed by the pacifist Albert Einstein, the physicists warned President Roosevelt about the possibility to develop the atomic bomb (enabled by the first nuclear fission experiments).  They urged the president to act - out of fear that Nazi Germany could be first to develop this weapon of mass destruction.

Some fifteen years, the release of two atomic bombs and the loss of over 100 000 lives later, Einstein (together with a group of other Noble Laureates) signed another document, the Russell–Einstein Manifesto, which highlighted the dangers of nuclear weapons for mankind and besieged decision makers to seek other problem solving strategies than nuclear annihilation.

After the first experiments on recombinant DNA opened the door to manipulating microbial – and, in sight at the horizon, also human - genomes, scientists gathered at the 1975 conference on gene therapy in Ansilomar, CA, to discuss the limits, which were to be imposed to the newly discovered technique.  It was the scientists themselves who committed to a voluntary moratorium, before rules for experiments on recombinant DNA were discussed at the conference.

When scientists found that a component of the bacterial immune system, the CRISPR-CAS9 system holds unprecedented potential for manipulating the human genome, the discoverers of the technology and other scientists called for a moratorium on heritable genome editing; in 2015, a few years after the seminal publication on the CRISPR from the 2020  Nobel Laureates Jennifer Doudna  and Emmanuelle Charpentier, and again in 2019 after the 2018 designer baby shock.

The promise of CRISPR CAS9

What aligns CRISPR CAS9 to those earlier earth-shaking discoveries?

The technique is as elegant, as it is simple, as impactful as it is scary; it allows researchers to precisely alter DNA; the DNA of adult humans, of unborn babies and of the human germline, of animals in the laboratory and of animals in the wild, of cultured crops and wild fauna, of microorganisms that produce biomaterials, drugs and vaccines.

It’s not difficult to imagine the good, the bad and the ugly outcomes of such a technique, ranging from the cure of genetic diseases to engineering desired genetic traits into children, from eradicating diseases such as malaria by releasing genetically modified mosquitos into the wild to causing unforeseeable environmental catastrophes by tempering with ecosystems, from fighting pandemics to newly designed biological weapons.

How much of this potential is already being realized? And how much of it is utopian or dystopian fantasy?

While numerous patients with genetic diseases and cancer set their hope in the potential of CRISPR-based therapies currently tested in the clinic, in 2018 we saw a glimpse of the darker side. The Chinese Doctor He Jiankui , performed a medically useless experiment of genetically modifying two twin girls on the single embryo stage to make them resistant to HIV. He felt the need to shout out his results to the public (on YouTube, a well-known source for high-quality, peer-reviewed scientific results).  But what about the scientists who don’t seek the spotlight? How many more experiments like He’s are performed quietly, despite a ban on germline editing in most countries? And what is happening outside the regulated laboratory environment?

The relative ease of using the technique has sprouted a group of so-called biohackers, which reversed the Don’t try this at home tactic and experiment with CRISPR kits in their living rooms and garages.

While arguably the complexity of germline editing and IVF, currently lies beyond the type of experiment you can perform in your living room, the question remains how dangerous the technique can be in untrained hands?

One thing is clear though - however risky, however promising we might consider the CRISPR technology, it is out in the world – and there is no pushing it back into the box.

Tune in next week for a deeper dive into the science underlying the CRISPR CAS9 technology, the challenges which lie ahead to use it for curing human disease and its use by biohackers.

Living inside the Andromeda strain? How life in times of the pandemic compares to the fictionalized apocalypse

Fictional works about apocalyptic diseases have been popular for decades, from Michael Crichton’s Andromeda Strain, to The Walking Dead, from Emily St. John Mandel’s Station Eleven to the Danish series The Rain (and many, many more…)

We’ve enjoyed watching people run for their lives, whilst grabbling with deep questions of humanity, have enjoyed super smart scientists in high-tech labs figuring out the riddling questions of their respective pandemics.

Now the actual pandemic falls short towards those works of fiction on several levels.

Thing is, the pandemic is boring in comparison to the fictionalized apocalypse. There are no zombies chasing us (like in The Walking Dead), we aren’t part of a top-secret government program (like in The Andromeda Strain) and we haven’t developed a gremlin-like fear of getting wet (Like the characters in The  Rain, where the virus is contained in the … yeah you might have guessed it …).

For those of us who’ve been lucky enough to have been spared the direct impact on our lives and livelihoods – we just sit in our homes, we bake bread, take pictures of the bread we bake, post the pictures of the bread on social media, look at the pictures of the bread that other people bake …

What’s the difference between the Corona Pandemic and those works of fiction?

The Speed

The viruses which cause the fictionalized pandemics, spread fast and kill fast.

While the Corona Virus moves in sneaky ways (aka aerosols & super spreaders) turning it into a fast-moving, global problem (unlike its cousins SARS and MERS), while it’s a more proficient killer than the flu (even if some people might try to tell us otherwise), it falls short behind those fictionalized super viruses that kill with a single glance in the eye (o wait, that’s the basilisk on Harry Potter) - but you get the drift.

The great plan behind it all

For many if not all pandemic stories there is some great conspiracy of government or terrorist groups or secret societies (which might even turn out to the same thing), which use the virus to achieve some evil goal.

A good conspiracy theory is helpful in explaining this unfair world. And let’s face it, the pandemic is the height of unfairness. Maybe that’s what brings the already Pre-COVID, hot to the boiling conspiracy belief of people to explode right now. Because wouldn’t it be nicer if there was some reason, like for example that the virus is made up by the deep state or that it spreads via 5G, and it’s possible to protect yourself by putting tinfoil around your head? For some people it seems better to believe in scenarios so ludicrous no sane fiction writer would dare to dream them up, than just accepting the evolutionary coincidence of a mutation event, of a jump from the unknown animal to the unknown patient zero to cause all the trouble we’re facing.

The world after

And then there’s the lack of perspective. In the typical pandemic story, disaster strikes, and the world is never the same after. And you don’t have to worry about keeping your job or about finding a supermarket that still stocks toilet paper, because you’re running from zombies, or evil rain, or your fellow humans who’ve turned hostile by lack of resources. The characters in pandemic stories don’t experience Pandemic Fatigue – when would they find the time. In the alternative scenario of the pandemic setting we find the disaster averted, after the super smart scientist saves the day and the world can return to normal.

What we experience is a slow-moving disaster that many people can’t even grasp. We know that fall and winter will be hard. We know to expect the next wave. But we just want it to be over with. And the super smart scientists that are working their asses off, to create vaccines and drugs, are smart enough to tell us we need to wait a little longer until disaster is averted.

Suggestions for the pandemically fatigued?

If you can - stay at home.

Bake some more bread.

Read an apocalyptic novel (recommendations welcome).

Go for a run and imagine hostile zombies/ rain/ people are after you to increase your running speed…

Can Corona headlines help decision making under uncertainty?

In times of crisis, decision making - which isn’t easy at the best of times – is made even harder.

Decision making during Corona times is ‘Decision making under uncertainty’.

Of course, we always face uncertainty when we ponder where to live (city or countryside, in our native country or abroad), with whom we want to share our lives (partners, children, pets, friends, family) and what we want to do for a living (earn money, save the planet, have fun or a mixture thereof).

For a naturally indecisive person like me this uncertainty might extend to the questions of what to wear (black or white sneakers), what to buy for dinner (salad or pasta) and which book to read next (mind-enhancing masterpiece or guilty pleasure romantic mystery) - questions that can easily keep my mind running amok for hours and prevent me from doing anything useful.

But since the pandemic the uncertainty has grown to unknown levels - and it doesn’t only concern the next years or decades, it concerns the next months, weeks or even days.

Will I still have a job?

Will I be able to travel?

And WHEN (for fuck's sake) can we go back to NORMAL, go back to making our choices on our own terms, instead of the virus’?

When can we go back to hugging our friends, to kissing our grandmother’s cheek, to sharing a drink with someone in a bar, to enjoying the blissful closeness of the crowd in a concert or at a sports event, without the constant risk of triggering an avalanche of new infections and endangering the risk groups?

If we want NORMAL, the virus has to disappear. To make it disappear we need one or more of the following:

·       A powerful vaccine, in enough supply to vaccinate large parts of the population

·       A treatment, which prevents serious disease courses of COVID19 and/ or longCOVID

·       Herd immunity

·       A miracle

We watch the headlines like hawks trying to glimpse pieces of information that will tell us when to expect any of those things to materialize.

There are headlines that show the progression of vaccine trials, of miracle cures with a sample size of n=1 or more… There are the shock moments of vaccine and drug trials being put on hold for safety concerns. There are scary headlines that show that immunity seems to be waning fast, of reinfections with severe course.  

Reading those headlines in the morning (because yes, I do admit to checking the news on my phone first thing in morning even though I should probably rather meditate or something) jerks around our emotions, can make or break our day.

Do those headlines help our decision making though? Do they tell us how long we have to wait until NORMAL returns?

As an emotional human being, I tend to like the thrill of a good headline. As a scientist, I admit that it might be worth the tedious work of reading some of the associated articles whole - though like many modern humans I seem to have developed a severe attention span issue (by the way, reader, great you’ve hanging in there, we’re almost done here).

Reading beyond the headlines dampens both fear and excitement. It seems likely that one or more of the numerous vaccine candidates will work and even if it doesn’t offer full protection might prevent serious disease courses. The same might be true for some of the approved or currently tested treatment approaches. The loss of immunity might not be as depressing as it appears on first glance, though herd immunity (at least for me!) still seems like a ludicrously dangerous approach, with too many lives at stake.

But none of these approaches currently seems to be the miracle, which will end the pandemic once and for all and none of them has a (believable) near-term time stamp on it, telling us when NORMAL will be back.

What does this mean for our decision making?

Postpone decisions until the Pandemic is over?

I would suggest a different approach.

Embrace the uncertainty.

Make important decisions now.

We might not know how the post-pandemic NORMAL will look like and when it will arrive but then, the future has always seemed more certain than it turned out to be…

Awoken by a kiss – Snow-White moments in science

In times of the Corona Pandemic, where new evidence emerges that the Corona virus affects other organs including the brain, lets  revisit a case of an amazing awakening of people who had fallen into a frozen state for decades after contracting the sleeping sickness in the early 1900s.

Awoken by a kiss

In the fairytale, Snow-White, the king’s daughter, takes up a shared living arrangement with a bunch of dwarfs after a big row with her stepmom. When things have just started to look peachy in her new life, she makes the unwise decision to bite into a poisoned apple and falls into a state of deep sleep.

Her dwarfy roommates find her unresponsive, almost frozen and nothing they try can reanimate their lady pal. Instead they arrange a fancy glass coffin for her – a kind if slightly creepy gesture.

But then, a prince arrives, and he seems to have a special mojo going that the dwarfs lack, because he revives Snow-White with a single kiss.

So far, so Disney.

But what about real life?

Frozen

What if our own brain, the command center of our spaceship, the organ which turns us into the masters of our fates, our bodies, our minds, what if this decision hub stops functioning the way it is supposed to? What if it stops giving commands to the rest of the body, trapping the mind in a frozen shell like a prisoner in an isolation cell?  Is that how Snow White felt, while stuck in her glass coffin, dwarfs bustling about – present but unable to move, to communicate?

There are different conditions of the brain that can induce such a frozen state: catatonic schizophrenia, drugs such as MPTP and brain inflammation.

Awakening

The neurologist Oliver Sacks describes this true-life Snow-White story in his book Awakenings. In the late 1960s, Sacks  was physician to a group of patients who were in a permanently frozen state after a 1920 epidemic of Encephalitis Lethargica, a disease which was dubbed the “sleeping sickness” for putting its victims into a Snow-Whitesk sleep state.

Sacks treated the patients with massive doses of the then newly discovered L-DOPA, a drug that is a precursor to dopamine, and which still a mainstay treatment in Parkinson’s disease, where Dopamine is notoriously absent in specific brain regions. and some of them responded to the drug and returned back to life. In his book Sacks tells the moving story of those individuals who woke up with a 30-year gap in their lives – a story few fiction writers would dare to dream up because it seems too outrageous for anything but a fairy tale or a soap opera.

Happily ever after?

Alas, the story does not have a Disney style happy end and neither do most other L-Dopa stories.

The effects of the drug aren’t permanent and come at the cost of severe side effects.

Some of Sacks’ awakened patients fell back into their frozen state and others experienced severe side-effects and personality changes.

For most Parkinson’s patients the initial effects of L-Dopa wear off with time, and they start to experience so-called OFF periods, in which the drug effect is gone. There are a number of side-effects, the most notable being involuntary movements, so-called dyskinesia, but also hallucinations or cognitive impairments.

A tale without hope then?

I would disagree. Even if L-Dopa does not provide a happily ever after, even though it isn’t a true cure, a magic bullet, the drug still allows the afflicted patients a continuation or return to something resembling a normal life for much longer than would ever have been possible without the drug. 

Wanna read more on the topic?

I recommend Dr. Sacks’ book Awakenings (or if you’re not into books you could watch the 1990 movie with Robin Williams and Robert de Niro.

Another great book on the topic is Jon Palfreman’s Brainstorms, in which the author, a  journalist and Parkinson’s patient himself gives an overview of the disease background, history of Parkinson’s research and new treatment options.

PCR AND HOW IT RELATES TO CSI Miami, COVID-19 AND DATING…

Why PCR, you ask… A method so popular its developer was rewarded the Noble Prize in chemistry in 1993 and that has its own song to boot?

What is it even for?

Take CSI Miami (or similar). The blond guy with the shades (ok, I just looked up his name on Wikipedia), so Horatio Caine looks down at a tiny speck of blood at the crimescene, faces the camera with a grave expression and says something profound like ‘DNA never lies.’ Well, if Horatio wants to get his bullet-proof DNA-truth he needs PCR.

Or take an afternoon talk show: the truth about the baby’s daddy is being revealed to a screaming audience. The verdict if sleezy guy A or guy B is going to be the one who tries to wiggle out of the child support payments (or who embraces the kid he never knew he had and vows to change his ways) – it’s determined using PCR.

Testing for viral infections from COVID to HIV? Often based on PCR.

And what does it do?

PCR amplifies DNA!

Many people consider DNA to be the most important molecule of life (other contenders for the throne would be RNA or proteins). Of note, some PCR techniques also measure RNA, like in the case of HIV testing, but today we’ll stick with DNA.

DNA is the long-term info storage of living organisms, handed over from parents to offspring. The molecule had a great spotlight moment when Rosalind Franklin, James Watson and Francis Crick discovered its double helix structure, in which two complimentary strands are wound around each other like a spiral staircase. This particular architecture for some reason seems to have boosted DNA’s popularity and turned it into the Rockstar among molecules. Even my grandfather who was generally more interested in history than biology, was a real fan of discussing the double helix. 

And how does it do it?

In explaining what PCR does to DNA, I’m going to borrow a few terms from the world of dating (admittedly, I am much more skilled at PCR than at dating though I haven’t done either in quite some time).

To understand what happens in a PCR, the famous structure of the DNA comes back into the game. We have two complimentary strands, in which four different molecules (bases) lie opposite one another and can pair in specific ways (always two bases go together as a couple and they don’t like to couple with anyone else).

If you break up the DNA strand (which you can do by increasing the heat, STEP 1) those bases turn into lonely single molecules. Out there in the cruel world of trying to find the right match, they are looking for their complementary bases to pair with. But they can’t do it on their own. They need the help of a matchmaker. This matchmaker is an enzyme called polymerase. This is where PCR gets its P from.

So now we have our key ingredients, the DNA of interest (recently single), the new nucleotides (available candidates) and the matchmaker enzyme (OK Cupid). But the bases are still a little shy, even with the matchmaker present they need a small boost to get going on the pairing cycle (like maybe a cocktail during the first date, STEP 2). This is where the primers, short complementary DNA sequences come in and tell the matchmaking enzyme where to start its coupling business. Once those primers have done their work, the matchmaker enzyme starts adding the free nucleotides (like serial dating, STEP 3).

With the newly made DNA strands, then the same thing starts over and over until you’ve got a lot (like really a lot) DNA molecules, resulting from a lot of dates.

But wait, how does this DNA dating answer our questions, like if the suspect can be convicted as the murderer, if sleezy guy A is the baby’s daddy or if you have a COVID-19 infection?

The primers, those innocent, short DNA stretches that get the pairing going are designed in a unique way, so the matchmaker polymerase will start adding molecules at exactly the same spot on the DNA every time. And if this unique piece of DNA isn’t present (because the suspect wasn’t at the crime scene or the man is not the baby’s daddy, or you don’t have a COVID-19 infection) then there will be no amplification of the DNA.

Note that PCR itself only amplifies the DNA, the scientists still need other techniques such as gel electrophoreses or DNA sequencing to visualize the DNA and learn about its composition.

PCR has its limitations of course, the main one is that the technique is only as good as its input DNA and the primers that are being used. But if done correctly, it is a powerful technique that can answer many important DNA questions.

I hope I could convince you that PCR is one of the magical methods. And what was it with this song again? Well here it goes if you want to cheer for the method again:  https://www.youtube.com/watch?v=x5yPkxCLads

Science fairy tales – Upcoming series

There are fairytales in science – and like the real, old-fashioned fairy tales they don’t always have a glossy finale, a kiss and a happily ever after.

There are tales in science that have a happy ending…

Those are tales of the moments of great discovery resulting from hard, year-long work or sometimes from pinch of serendipity – like the almost accidental discovery of Penicillin a drug that helped shaped the modern world by significantly contributing to the increase in life expectancy - from a meager 47 years at birth at the beginning of the 20th century to close to 80 years (in the US). A happy ending for the scientist Alexander Fleming (who’d forgotten to throw out his experimental plates before going on vacation), and a happy ending for humanity who suddenly had a new ally in the war against the microbial invaders.

There are darker tales too…

Dystopian scenarios introduce us to a world in which the scientific discovery feels like an already open Pandora’s box. One of the things that emerged from this box recently is gene editing, a technique that allows changing the genomes of species from mosquitos to humans in an unprecedentedly simple way, so simple in fact that you could do it at home with a preordered kit (if you are in a country which hasn’t banned the technology). A group of researchers who had discovered gene editing, the ones who had opened Pandora’s box, called for a moratorium on gene editing early on, before the public or politicians had caught wind of the potential dangers of the technology (we will read a lot more on gene editing in upcoming posts).

In equally dystopian scenarios the scientific discoveries that have protected us from hostile outside invaders that want to hijack our bodies – vaccines and antibiotics – fail due to human unwillingness to behave reasonably.

There are science tales that almost feel like horror stories…

Maybe one of the most gruesome stories of modern science is that of lobotomies, in which a steel spike (the most prominent lobotomist Walter Freeman later changed to icepicks) is pushed into a person’s frontal brain to cure all kinds of symptoms from depression to schizophrenia, often leaving patients devoid of the symptoms, but also devoid of anything that resembled their former personality. Thousands and thousands of lobotomies were performed and the scientific community (or at least a part of it) was so convinced of the merits of lobotomy that its discoverer Egas Moniz, even received the Noble Prize for it.

Next Friday, we’ll start the science fairy tale series with one of the happy Science Tales – a true Snow-White story in which frozen people can be awoken with a kiss (though no dwarfs will be involved)…

4 reasons why science can’t give us the answers during a time of crisis (3/4)

After introducing reasons 1 &2 yesterday, lets discuss two more today. If you haven’t read yesterday’s post yet, and you have a few extra minutes check out reasons 1& 2 there…

3.      Scientists aren’t altruistic robots

Scientists aren’t selfless creatures who care only about doing good for humanity. Though these characteristics might apply to some individuals, scientists as a whole are like any other tribe of human beings. They have to be political to negotiate their way through the demands of the academic system and the funding agencies. A good pinch of narcissism helps as well, it makes it easier to survive rotating around the same research topic for decades, while giving up so much of your free time for often little reward – be it recognition or money. If you attack the scientist’s pet theory, you run the risk of attacking the scientist. If you ask the scientist a question the answer might be driven by more than the hard facts of the data.

4.      Science isn’t free

At least not completely. This doesn’t mean that biomedical scientists are the slaves of the pharmaceutical industry. But there’s a more subtle manipulation at play. Biomedical research costs a lot of money. The math is easy: the more money you pour into a research field, the more people want to study it.

There are different motivations for the pharmaceutical industry, government and private foundations to dedicate funds to certain research areas. One such motivating factor is the urgency of the topic. The concentrated funding effort into research on HIV/ AIDS has turned the disease from a death sentence into a manageable and maybe even curable condition. Unfortunately, other motivations for choosing where funds are headed are less humane. The pharmaceutical industry focuses on areas where money can be made. The funds that go into antibiotic research for example are so limited that we’re running blind-sided into an approaching catastrophe of antibiotic resistance.

Private foundations like the Bill and Melinda Gates foundation are trying to rectify this situation by donating to causes that have little prospect of creating revenues, including infectious and rare diseases. It’s a thing to be grateful for, but this type of funding oligarchy induces another kind of bias.

The understudied areas in biomedical science are those were we lack the answers most urgently and the Corona pandemic might be a wake-up call to seek answers in a societal effort.

So, let’s get back to our original quest: what are the correct answers to those questions?

An honest answer from a scientist, to a question like ‘Does a facemask protect against the virus?’ might sound something like: ‘I have evaluated three studies and none of them has gathered sufficient data to answer your question. There are probably three other studies I don’t know about.’  OR ‘I don’t have time for this, I’m busy with a private feud with one of my coworkers in the laboratory who wants to be first author on my paper.’ OR ‘I can’t tell you, there’s no money in this field of research because no one has cared about it until three months ago.’

That’s not what you want to hear the scientist say, and it likely won’t be the answer in an interview.

But maybe not having simple answers to complex scientific questions (even the crisis questions) isn’t that bad, as long as we manage the expectations of what we can deduce from scientific data (a single study in ten patients usually does not hint to a new wonder drug) and as long as everyone applies their own common sense (don’t try the supposed wonder drug until it’s proven to be safe). 

The problem is that in science – and in life – things are rarely as easy as we’d like them to be. 

4 reasons why science can’t give us the answers during a time of crisis (1 &2)

‘So what is the correct answer to this question. You’re a scientist, you should know!’

Should I? I’ve been a biomedical scientist for years. Still, I could name only a few scientific questions to which I know the correct answers. Among the questions that I, like so many other scientists, can’t answer with certainty are:

The big questions: ‘Will we find a cure for cancer?’ OR ‘What’s the origin of the universe?’ OR ‘How do we stop climate change?’

The questions beloved by media: ‘Will eating butter kill me or was that margarine, or maybe both?’ OR ‘Will drinking a glass of red wine ward off heart disease?’ – I mean wouldn’t it be nice if butter and wine were good for my health – even if I might drink two glasses on occasion?

The crisis questions: ‘How does the Corona virus spread?’ OR ‘Am I protected from the virus by wearing a facemask and protective gloves?’ OR ‘How long does it take to develop a vaccine or drug?’ 

What are the correct answers to those questions?

While many scientists voice their opinions, the media, the politicians and the public aren’t always happy with the answers - too vague, too many contradictions, too many maybes.

There are many reasons why science doesn’t provide easy answers to complex questions. Here are four of them:

1.      The results of scientific studies aren’t facts set in stone

Science works by hypothesis generation, followed by falsification of the hypothesis, followed by new rounds of hypothesis generation and falsification (yep, it does get tedious), until we reach a hypothesis that sticks. The method of falsification is the scientific experiment. If we want to believe the results of such an experiment, we need to be sure they’re more than coincidence and that they aren’t driven by bias. Any study, no matter how perfectly designed, no matter how ethically pristine will contain a certain bias.

Only if different researchers do the same study again and again and find the same results, do we really believe the hypothesis.

Therein lies the problem.

If you do the same study over and over, you will get a variety of different outcomes, some supporting the hypothesis, some contradicting it. So if you ask a scientists a seemingly simple question about a hypothesis (like if wearing a facemask protect you from a virus), you might get a variety of answers, depending on which study the scientist believes in and if the scientist in question even knows all the studies that are out there.

2.      Not all scientific data are being recognized

Which brings us to the next problem. The fact that the scientist has done the experiment and found the results doesn’t mean the scientific community recognizes them. If the results are negative, the scientist will often choose not to publish them at all. And even published data simply disappear into the vacuum of the scientific publication landscape. Maybe the theory sounds too crazy, maybe the scientist is not in the right place at the right time, maybe the advocates of the opposing theory are too powerful.

And then there is the question of the sheer number of scientific publications. Not even the most experienced expert in a field will find the time to read all the literature on a certain topic. You could try, but it might take more than a lifetime.  And that wouldn’t leave any time for experiments, or sleep, or a glass of wine with friends…

Tune in again tomorrow for reasons number 3 and 4…

Searching for the magic bullet – high hopes, desperate measures and bitter disappointments

Searching for the magic bullet

An infectious lung disease spreads across Europe. The disease can be transmitted through the air – you can catch it if the person next to you coughs or sneezes or just talks.

Nope, not Covid-19.

Tuberculosis in the 19th century.  

Tuberculosis has been around for as long as humans existed. But after the industrial revolution, the disease tightened its grip on newly urbanized Western Europe, until it turned into a real pandemic. While there was some air of tragic heroism created around the victims of the ‘romantic disease’ – how can you not cry when Mimi dies in La bohème - in the end there is nothing heroic about it. Tuberculosis was (and in many parts of the world still is) nothing but an ugly, life-threatening lung disease.

Just like we hope to find a drug or a vaccine for Corona virus/ Covid-19 – a magic bullet that will rid us of the threat the disease poses to our lives, our livelihood and our freedom once and for all - the people of the 19th century were hoping for a cure for tuberculosis. And like us today, they wanted their magic bullet sooner rather than later.

Lucky for them, the scientific world had just been turned upside down by the discovery that many diseases are not caused by internal imbalances of the bodily humors but by tiny, hostile invaders – microorganism. In the 1880s, the German microbiologist & physician Robert Koch found the bacterium which causes tuberculosis - Mycobacterium tuberculosis (for some reason we scientists can’t resist writing the Latin species names in italics, since that’s the way we learn it at university).

A little competition is good for business

In the newly founded field of microbiology, there were two titans, the French Louis Pasteur and the aforementioned Robert Koch. The two men were locked in a scientific wrestling match for large parts of their careers, trying to trump the other’s successes, trying to be the first to make the discovery. If you want to win a race, sometimes you have to take risks.

They did.

Pasteur vaccinated children with an untried rabies vaccine. He was lucky, it worked.

Koch developed a supposed wonder drug to treat tuberculosis and in 1890 let it loose on the public. He wasn’t as lucky as his French colleague, the concoction he sold under the name tuberculin didn’t cure Tuberculosis.

History forgave him this epic failure. He was awarded the Nobel Prize in 1905 and he is remembered for his successes and not for this one big screw-up. The question is if his contemporaries, who’d been treated with the ineffective drug forgave him so easily.

Giving him the benefit of the doubt, I would say that Koch meant well. His biography does not give the appearance of a mountebank, a scientific scam artist who’d set out to cheat his patients. He had good intentions. But he became impatient.

The Principle of Hope

Good intentions can take you a long way.

Hope and daring can take you a long way.

But they can only take you so far. 

If you read the news today you see scientists and pharma representatives and politicians (and plenty of other people who feel the need to voice their opinion) speculate passionately about the earliest release date of a vaccine and about the potential miracle drugs (and some other scary ideas we’d rather not discuss here).

Vaccine development usually takes years up to decades. To show the vaccine works, you have to vaccinate a healthy person and wait until that person encounters the pathogen in the wild. An alternative are so-called challenge trials – in which volunteers are exposed to the pathogen in an experimental setting. In the case of Covid-19, with its unpredictable effects in different individuals, this approach is ethically questionable.

And, there is no guarantee that any of the vaccines candidates under scrutiny will work. Two of the most promising candidates are the vaccines from moderna and BioNTEch/ Pfizer. Both companies rely on the so-called mRNA technology and have seen a hype even before the Covid-19 pandemic, reflecting the hopes set in the technology.

But hope doesn’t have to mean success.

Another contester is a DNA vaccine from the University of Oxford, which like the other candidates is still in early stage development. Nevertheless, the ‘Vaccine king of India’ (to be honest, anyone who’s called the King and who isn’t Elvis makes me suspicious) is starting mass production of the basically untested vaccine.

Hope is good. Hope is necessary. But hope isn’t enough to will a miracle drug or vaccine into existence. And there is a fine balance between necessary daring, and using people as guinea pigs for untried concepts, as Koch and Pasteur did.