The Exponential Ride

By John Mauldin

I've got to admit it's getting better (Better)
A little better all the time (It can't get no worse)
I have to admit it's getting better (Better)
It's getting better since you've been mine
Getting so much better all the time

—Getting Better, Paul McCartney and John Lennon, 1967, “Sgt. Pepper’s Lonely Hearts Club Band” album

The last year brought exponential growth in, among other things, use of the word “exponential.” It is now the go-to term when you want to say something is “growing super-fast.”

As humans, we tend to think in terms of linear growth—whatever is happening immediately around us in shorter time periods. Accelerating, exponential growth is harder to grasp. Exponential growth means the rate of growth increases with time, just like a car goes faster the more you press the gas pedal.

“Exponential” has become popular recently to describe the way a virus spreads, if nothing stops it. When one person infects two others, each of whom infects two others, who each infect two others and so on, the numbers can quickly get out of hand. Exponentially so.

But exponential growth isn’t always scary. 

Compound interest is exponential and we all enjoy it (when we’re the lender, at least). 

Moore’s Law, which says the number of transistors on integrated circuits doubles approximately every two years, is another example of extremely useful exponential growth. 

The chart below starts in 1970, but Moore made the observation in 1965.

Source: Our World in Data

The number of transistors on a microchip “only” doubles every two years. But that took it from 1,000 transistors to 50 billion in 50 years. Literally, 50 million times more powerful.

But it’s even better. If you go back to the late 1940s when transistors were first being developed, having 1,000 transistors on something called a microchip was barely a dream. But with time and literally tens of thousands of patents and innovations, etc., we got to 50 billion. People have been proclaiming the end of Moore’s law for decades. I’ll take the other side of that bet and we are just exploring the edges of quantum computing.

Read a little about the chip industry’s growth and you’ll see words like “surprise” and “accidental” discoveries. You’ll also see that it didn’t happen in one place at one time but was literally exploding all over.

But the exponential growth of the microchip would not have been possible without the exponential growth of all sorts of technologies and innovations developed over the previous 100 years. That’s the amazing thing about innovation. Or, more broadly, we could just call it “progress.”

Humanity is constantly learning and improving. These improvements build on themselves in an exponential process. That’s why daily life changed far more in the last 200 years than it did in the prior 20,000 years. The rate of growth accelerated. And that’s why we will see more change in the next 20 years than we have seen in the last 200.

Today we enjoy living standards far higher than even royalty did not so long ago. Yes, we have problems, serious ones, but we also have advantages. We know we can make the world better because it is getting better. And it’s getting better all the time, at least over time.

Occasionally I devote a letter to highlighting good news—positive things that are happening all around us, often unnoticed or unappreciated. 

The last one was in January 2020, just before the pandemic consumed our attention (see Looking on the Bright Side). We’ll get back to the problems of the day later, but today I want us to appreciate the positive. There’s a lot of it out there. 

And any serious investor should pay attention because technological innovation is where the real financial upside is (along with, admittedly, a lot of dead-end alleys).

Before we begin, I’m very happy to report that our second all-virtual Strategic Investment Conference is shaping up to be one of the most star-studded SICs we’ve ever had. We have confirmed close to 40 speakers now, and many are celebrities in their respective fields. And yes, we will be devoting some time to some of the technological innovations that are just now appearing, with some of the people who are making them appear.

We haven’t unveiled the full list of speakers yet but for more details, I invite you to watch a short personal video message I recorded a few days ago. On the same page, you can also pre-order your SIC 2021 Pass at a 50% discount (or more, if you are one of our Alpha Society members). I hope to see you in May!

Pandemic Pluses

This year’s top good news, by far, is the COVID-19 vaccines. It was a mind-boggling scientific, manufacturing, and distribution achievement. To have a vaccine at all is amazing; to have several of them only a year after the virus was identified is unprecedented. This kind of work once took decades. Operation Warp Speed was indeed a triumph of human work, cooperation between the private and public sectors, effort, and ingenuity.

This happened in part because scientists had been working on the underlying methods and technologies for a long time, not knowing they would be useful in a pandemic. You can read the whole gripping story in The Atlantic by Derek Thompson.

Briefly, “messenger RNA” (ribonucleic acid) is a genetic substance that tells your cells which proteins to make. Researchers in various places realized long ago that manipulating RNA could be quite useful, but exactly how to do it was elusive.

It turns out that Hungarian scientist Katalin Karikó discovered mRNA back in 1978. She eventually ended up at the premier epidemiological university in the United States, the University of Pennsylvania, where she worked on her discovery with other scientists. Eventually in 2000 they began to see some success. (I have probably walked past what was once her office on my tours of the facility.)

Private companies began working on mRNA products, with Moderna in the US and BioNTech in Germany eventually cracking the code. US pharmaceutical giant Pfizer had made a deal with BioNTech in 2018 to develop an mRNA flu vaccine. When SARS-CoV-2 struck, they pivoted quickly. The result went into my arm a month ago and again this week (and I hope yours as well). The technology they developed may well lead to other life-saving medicines, like a malaria vaccine (with a variation of mRNA technology) and individually tailored cancer treatments.

I want to focus a little bit on how incredibly successful the actual vaccine is, and to highlight some of the misinterpretations of statistics by the public. I get a long email from Justin Stebbing every day discussing the massive amounts of research on COVID that came out in just the recent few days. 

This crossed my desk this week:

So, with a 50% effective vaccine, we have a 50% chance of contracting COVID-19, and with a 95% effective vaccine, we have a 5% chance… right?

Actually, the news is much better. 

Consider what that “95% effective” statistic actually means. 

As The New York Times' Katie Thomas explained, the Pfizer/BioNTech clinical trial engaged nearly 44,000 people, half of whom received its vaccine, and half a placebo. 

The results? 

“Out of 170 cases of COVID-19, 162 were in the placebo group, and eight were in the vaccine group.” 

So, there was a 162 to 8 (95% to 5%) ratio by which those contracting the virus were unvaccinated (albeit with the infected numbers surely rising in the post-study months). 

Therein lies the “95% effective” news we’ve all read about. 

Or the 90% real world stuff I sent round yesterday.

So, if you receive the Pfizer or equally effective Moderna vaccine, do you have a 5% chance of catching the virus? 


That chance is far, far smaller: Of those vaccinated in the Pfizer trial, only 8 of nearly 22,000 people, less than 1/10th of one percent (not 5%), were found to have contracted the virus during the study period. 

And of the 32,000 people who received either the Moderna or Pfizer vaccine, how many experienced severe symptoms? 

The grand total, noted David Leonhardt in a follow-up New York Times report: one.

[German Scientist] Gigerenzer says that his nation suffers from the same underappreciation of vaccine efficacy. 

“I have pointed this misinterpretation out in the German media,” he notes, “and gotten quite a few letters from directors of clinics who did not even seem to understand what’s wrong.” 

“Be assured that YOU ARE SAFE after vaccine from what matters—disease and spreading,” tweeted Dr. Monica Gandhi of the University of California, San Francisco.

Of 74,000+ participants in one of the five vaccine trials, the number of vaccinated people who then died of COVID was zero. The number hospitalized with COVID was also zero:

This is simply mind-boggling, in terms of not just the speed at which the vaccines were developed but also their efficacy. 

But just like the 442,000 Teraflop per second computer (the world’s fastest computer now in Japan), the successful vaccine would not have been possible without the multiple decades of work developing it, let alone the even longer period of research prior to the discovery of mRNA. 

Moderna literally had a working vaccine model within 48 hours after learning the DNA sequence. Six weeks later, it shipped its first vaccine batches to laboratories in Maryland to begin human trials. 

The summary from The Atlantic article mentioned above?

The triumph of mRNA, from backwater research to breakthrough technology, is not a hero’s journey, but a heroes’ journey. 

Without Katalin Karikó’s grueling efforts to make mRNA technology work [in 1978], the world would have no Moderna or BioNTech. 

Without government funding and philanthropy, both companies might have gone bankrupt before their 2020 vaccines. 

Without the failures in HIV-vaccine research forcing scientists to trailblaze in strange new fields, we might still be in the dark about how to make the technology work. 

Without an international team of scientists unlocking the secrets of the coronavirus’s spike protein several years ago, we might not have known enough about this pathogen to design a vaccine to defeat it last year. 

mRNA technology was born of many seeds.

The vaccines may be what gets us out of the pandemic, but the experience drove some other unintentional innovation, too. 

One was remarkably simple: Remote doctor visits. 

Many medical issues can be handled with a simple conversation, but (at least in the US) it rarely happened for legal, liability, and insurance reasons. 

The pandemic compelled all the players to cut through those barriers. 

I don’t think we will be going back.

This also illustrates the exponential growth principle. 

Now that remote medicine is allowed and people (both providers and patients) are getting comfortable with it, we will expand the range of services delivered that way. 

Technology will be the key—or rather, a bunch of technologies working together. 

Virtual reality cameras and visors, 5G bandwidth, haptic sensors to convey “touch” without being there—all will speed up the process and should lead to better outcomes.

But even as the pandemic unfolded, other innovation continued. Let’s look at some more examples.

Food Future

The last year also gave many of us a new relationship with our food. 

With restaurants closed or limited, we did more of our own cooking.

In fact, our food habits and methods are always changing. 

Many plants we eat simply didn’t exist in their current form even a century ago. 

They have been cross-bred and manipulated into what we know now. 

That process is continuing as several companies now offer plant-based meat substitutes. 

As often happens with new technologies, prices are falling and people are finding new uses for the products.

My friend Professor Jesse Ausubel at Rockefeller University wrote to me last week about a joint venture between US and Chinese companies making a new “single-cell protein” substance called FeedKind. 

It is manufactured by fermenting natural gas with naturally occurring bacteria 

The resulting pellets are used to feed fish. 

Used instead of soy, it will free up huge quantities of land and fresh water.

Material Factors

Some of the most amazing breakthroughs are also the most basic: the materials we use to build everything else. 

Hydrogen, for instance, is the most abundant element in the universe yet we have long struggled to isolate and make use of it. 

This is changing.

The current process for producing hydrogen consumes a lot of energy itself, and also emits large amounts of greenhouse gases. 

Another method called electrolysis is simpler and cleaner. 

All you need is water and electricity. 

The electricity can come from renewable sources. 

That means hydrogen can (in theory) be produced almost anywhere, reducing the need to haul fossil fuels around the world.

Beyond hydrogen, other materials science breakthroughs are brewing everywhere. 

My friend Peter Diamandis recently talked about graphene, which is basically a sheet of carbon just one atom thick, nearly weightless but 200 times stronger than steel. 

He calls it a “super-material” for obvious reasons. 

The applications are endless.

He also wrote about nanotechnology—manipulating matter at super-microscopic levels. 

This is a bit unbelievable so I’m just going to quote him directly.

Progress has been surprisingly swift in the nano-world, with a bevy of nano-products now on the market.

Never want to fold clothes again? Nanoscale additives to fabrics help them resist wrinkling and staining.

Don’t do windows? Not a problem! Nano-films make windows self-cleaning, anti-reflective, and capable of conducting electricity.

Want to add solar to your house? We’ve got nano-coatings that capture the sun’s energy.

Nanomaterials make lighter automobiles, airplanes, baseball bats, helmets, bicycles, luggage, power tools—the list goes on.

Researchers at Harvard built a nanoscale 3D printer capable of producing miniature batteries less than one millimeter wide.

And if you don’t like those bulky VR goggles, researchers are now using nanotech to create smart contact lenses with a resolution six times greater than that of today’s smartphones.

And even more is coming. Right now, in medicine, drug delivery nanobots are proving especially useful in fighting cancer. Computing is a stranger story, as a bioengineer at Harvard recently stored 700 terabytes of data in a single gram of DNA.

The applications are endless. And coming fast. Over the next decade, the impact of the very, very small is about to get very, very large.

Again, all this is coming now. And as I described above, the real impact is exponential. Using nanotechnology to solve these problems will free up the productivity currently being applied to them, so it can be multiplicatively used for something else. What would that be? Probably things we can’t presently imagine.

While we are approaching the limits of lithium-ion batteries, there are literally scores of new technologies being developed which will far surpass current technology. The ultimate green energy, fusion energy, is fast becoming more than a pipe dream. There is a revolution in agricultural production (I am somewhat involved with it) that will completely disrupt current production cycles over the next 20 years. A little slower than Moore’s Law, but just as powerful.

You may have missed that last year Brown University scientists began wirelessly connecting the human brain in quadriplegics. An electrode array is attached to the brain’s motor cortex and then high-speed networks allow the patient to communicate. We are not all that far from the day when, if you choose, you will be able to “talk” directly to your computer simply by thinking.

Entrepreneurial Shifts

Our most important natural resource, by far, is the human mind. Any one of them has astonishing potential all by itself. When we put them together, true magic happens.

As you know (because I and others have lamented it), this pandemic/recession has destroyed hundreds of thousands of small businesses all over the world. But it didn’t destroy the entrepreneurs who founded them. I believe many will do what comes naturally to them and start more businesses—hopefully better than those they lost.

Transitions are hard but often lead to a better place. I believe some wonderful new ideas—and very successful businesses—will emerge from this time. I can’t wait to see what they are.

We literally live in one of the most exciting periods in all of human history. Oh, did I not mention the possibility that we might live a great deal longer than previous generations? 

Maybe in the next positive letter…

Root Canals, Travel, and Some Speculation on the Future of COVID

Over the last 40+ years, I have had maybe 4–5 root canals. 

They are never pleasant. 

I have another tooth which is beginning to become a nuisance, so I went to my local dentist, Carlos Martinez, and he took an X-ray, which he then shared electronically with another doctor a few miles away as they discussed my prognosis. (I have to admit the technology he uses is far superior to whatever the dentist I used in Dallas had.) 

Basically, it is going to become a problem at some point. 

So next week I get a root canal, and I hope the technology has improved so that it will go a little less painfully.

I am looking forward to being able to travel after the SIC. I truly hope that more of the country opens up, including Puerto Rico. 

But to do that we really need to encourage everyone to get their vaccinations. 

Then we can relax these intrusive precautionary measures and people will get on with their lives, both personally and professionally.

That being said, we will probably face versions of COVID-19 for years. 

New variants will develop in countries that have not been able to vaccinate and achieve herd immunity. 

The doctors and scientists I talk with fully expect that we will need periodic booster shots for a few years at least. 

But I know of several companies working on a “universal” vaccine.

Beyond vaccines, technologies are being developed that will constantly clean viruses and bacteria from our homes and gathering places, with no harm to human beings. 

Further innovations of that technology will be available before the end of the decade and I think will become ubiquitous.

A quick reminder to those who aren’t yet in the club: Follow me on Twitter.

And with that, I will hit the send button and wish you a great week!

Your pursuing his own innovation businesses analyst,

John Mauldin
Co-Founder, Mauldin Economics

The medicine is the message

Covid-19 vaccines have alerted the world to the power of RNA therapies

And the molecule has many more tricks up its sleeve

Molecular biology is not a popularity contest. 

But if it were, it would be a partisan one. 

The evolutionary biologists would pledge their allegiance en masse to dna. 

The sequences contained in its regular coils knit together the stories of almost all life on the planet. 

Pharmacologists, being of a more practical bent, would instead vote for proteins. 

Proteins are not about sequence, but about shape; their complex, irregular outlines, and the ways that they can change, allow them to do almost all of the biological work that gets done in cells. 

And it is thanks to the way that particular drug molecules fit into those shapes that almost all drugs have their effects.

There would be only a small following for ribonucleic acid (rna), widely seen as a helpmeet molecule. 

It could be argued that the production of rna is dna’s main purpose; it is certainly true that the production of proteins would be nowhere without it. 

But it is a backstage operator, not a star; hewing wood and drawing water, hard working but hardly glamorous, appreciated only by devotees.

Or at least that was the case until vaccines made of rna started giving protection against covid-19 to millions of people around the world every day. 

Now Cinderella has gone to the ball. 

Not only are rna vaccines being considered for all sorts of other diseases, some of which have yielded to no other approach; other pharmaceutical uses of rna look set to come into their own, as well. 

The way molecular biology is applied to medicine seems to be in the throes of revolution.

Incarnation incarnate

The great unifying truth of molecular biology, uncovered during the intellectual revolution which followed the discovery of dna’s double-helix structure, is the way in which the worlds of shape and sequence are linked. 

The shape of a protein depends on the intricate way in which the chain of amino acids of which it consists is folded up. 

That depends in turn on the order in which amino acids of different types are strung together on that chain. 

And the order of the amino acids is a crucial part of the genetic information stored in the dna sequences of the cell’s genome.

The transfer of information from the staid archival form it takes in the genome to its active physical instantiation in the machineries of the cell depends on rna, a molecule in which both sequence and shape play crucial roles. 

The gene sequence is first copied from dna to rna; that rna transcript is then edited to form a molecule called a messenger rna, or mrna (see diagram).

The end of the mrna molecule is formatted into a distinctive shape which is recognised by ribosomes, complex pieces of machinery composed of dozens of proteins draped around another set of rna molecules. 

With the help of yet more rna molecules—little ones called trnas which stick to the mrna sequence three letters at a time—the ribosome translates the genetic message into the protein it refers to by creating a chain of amino acids as it moves along the message.

This is the mechanism exploited by the rna vaccines developed by BioNTech, a German biotechnology company based in Mainz, and Moderna, an American one from Cambridge, Massachusetts, against sars-cov-2, the virus which causes covid-19. 

The companies mass produce the rna sequence describing the distinctive “spike” protein, which studs the outer membrane of the virus, formatted so as to look like a natural mrna. 

These rna molecules, wrapped in little fatty bubbles called liposomes are injected into patients, where the liposomes smuggle the mrna into cells. 

Ribosomes pick up on the mrna format and read the sequence, thus producing the spike protein. 

The immune system learns to recognise the spike which the vaccinated cells are producing and stores away the memory of how to do so. 

This allows it to mount a swift response if it later comes across the same protein on the surfaces of viral particles and infected cells.

This ability to get cells to churn out proteins for which their dna contains no genes is, in itself, enough to open up swathes of new therapeutic territory. 

But it is not the whole story. Cells make vast amounts of rna that does not describe proteins. 

Its ability to recognise specific genetic sequences makes it useful for all sorts of processes, including turning the translation of genes on and off. 

Its ability to fold itself into particular forms—hairpins, loops and the like—makes it good at interacting with proteins.

This alphabet soup of rnas (see table) seems to function a bit like a computer’s operating system, mediating the relationship between the cell’s hardware and its software. 

Many of the details of how this works remain obscure. 

But some are understood well enough for a lot of brainpower and money to have been poured into attempts to hack the operating system for therapeutic purposes.

These abilities should enable drugmakers to head upstream from the proteins whose shapes they have long studied into the realms of sequence. 

Where previously they targeted proteins which were already present, now they can in principle target the processes which control which proteins get made in the first place, adding helpful new ones to the roster and crossing harmful old ones off. 

There are rna-based drugs in clinical trials for the treatment of cancer, heart disease and numerous inherited disorders—as well as brain diseases such as Alzheimer’s and Parkinson’s.

Moreover, rna’s mixture of sequence and shape means that in many of these areas the once-haphazard process of drug discovery, long dependent on matching the shape of small synthetic molecules to the crannies and crevices of the proteins they targeted, can itself be systematised. 

A sequence which recognises, or forms a part of, one gene can be switched out for a sequence tailored to another. 

When what an rna drug does depends on its sequence, its target and action can be modified by the click of a mouse.

The medicine is the message

Both the firms with mrna vaccines on sale had other vaccines in the pipeline before covid-19 struck. 

It is part of the appeal of the technology that they were able to turn on a sixpence and refocus their efforts on sars-cov-2 as soon as the sequence for its spike gene was released last January. 

Now they are both getting on with what they had planned beforehand. 

Moderna is looking at vaccines to fend off infection by cytomegalovirus (a herpes virus which causes neurological problems in newborns), three lung viruses which cause respiratory disease in young children and Zika, a mosquito-borne virus found mainly in the tropics. 

BioNTech is focusing more on developing vaccines, and other treatments, with which to treat a wide range of cancers.

Cancer cells tend to have peculiar constellations of proteins on their surfaces, including both normal ones that are overexpressed and, more intriguingly, mutant forms peculiar to the development of that tumour. 

Comparing the genes expressed in a patient’s healthy cells with those used by their tumour cells reveals which mutant proteins the cancers are producing; mrnas for those proteins can then be incorporated into a vaccine.

Produced as a result of vaccination, the proteins can engender a vigorous immune response the cancer itself does not—part of being a successful tumour is deploying mechanisms that stop the immune system from coming to grips with you. 

According to Ozlem Tureci, BioNTech’s co-founder, the firm has 500 patients enrolled in clinical trials for cancer. Moderna is pursuing similar ideas.

BioNTech is also testing mrna vaccines aimed at overexpressed but unmutated proteins. 

Moderna, meanwhile, is looking into vaccines that train the immune system to recognise proteins created by common mutations in kras, a gene implicated in about 20% of human cancers. 

CureVac, based in Tübingen, an mrna firm which also has a sars-cov-2 vaccine in trials, is conducting trials of a vaccine for non-small-cell lung cancer.

Vaccination is not the only way that mrna injection might fight viruses and tumours. 

The technique could also be used to get cells to produce therapeutic proteins that are currently administered through injection or infusion: interleukins and antibodies.

Designer antibodies are a massive faff to make in industrial quantities; getting patients’ cells to take on the manufacturing duties instead would be a great step forward if it proved practical.

There are many other sorts of proteins which can be stimulated to therapeutic effect. 

A project on which Moderna is collaborating with AstraZeneca, a pharmaceutical giant, delivers the mrna for a protein which encourages the regrowth of blood vessels. 

The idea is that the therapy, now in phase 2 clinical trials, could stimulate the growth of new cardiac blood vessels after heart attacks.

Getting the body to produce a protein it needs just for a short while—an antibody, say, or a growth factor—is one thing. 

But what about a protein that it needs on an everyday basis, but lacks the gene for? 

Such genetic diseases have always been the most obvious targets for gene therapy—treatments which add a missing gene to a patient’s cells, or repair a broken one, thus allowing them to make a protein they have hitherto lacked. 

But at least some such conditions might instead be treated with mrna. Inserting a gene might be more elegant—but getting it in the right place and regulated in the right way is challenging. 

If mrna treatments get the job done, they might offer a nice alternative.

There are thus mrna treatments being studied for phenylketonuria, a metabolic disorder which requires sufferers to restrict their diets for their entire lives; glycogen-storage disease, which enlarges the liver and kidneys and stunts children’s growth; and propionic and methylmalonic acidemias, two illnesses in which the body cannot properly break down proteins and fats. 

All are conditions that gene therapists are looking at, too.

That BioNTech, Curevac, Moderna and some others now have all these projects on the go is largely down to the fact that they have spent many years developing the basics of their platforms. 

Many hurdles had to be crossed before they could get cells to accept and act on messages from beyond; the rna had to be subtly toughened up so that it would not itself fall prey to the immune system or get dismantled inside cells; the right lipids had to be found for delivery, sometimes tailored to particular tissues like those of the liver or lymph nodes. 

The potential inherent in the idea meant that their work was not completely ignored; in 2018 Moderna’s ipo valued the company at $7.5bn, a record for the biotech sector. 

But biotechnology has a long history of proving biology to be messier and more contrary than those seeking to exploit its loopholes expect.

Stop making sense

Scepticism was also warranted, it seemed, by the fact that messing around with rna had been through bursts of popularity before. 

One of the very oldest companies in the field, Ionis Pharmaceutials (known as Isis until that name was appropriated by a would-be caliphate) was founded in 1989. 

Its intention, then and now, was not to make use of mrna, but to hobble it.

The sequence of an mrna molecule carries the same information as can be found in the gene which served as its template; but thanks to the way rna is made it carries it in a complementary way. 

Where the dna has a letter called C for cytosine, the rna will have G for guanine; where the rna has a C the dna will have a G, and so on. 

Complementary strands stick together; that is what keeps dna molecules paired up in double helices. If you introduce an mrna to a molecule with a complementary sequence the two will stick together, too, rendering the mrna useless (see bottom deck of diagram above).

Again, getting the neat idea to work in ways that helped proved hard. 

It took Ionis a quarter century to start getting its “antisense” drugs to market on a regular basis. 

It now has three: nusinersen, approved in America in 2016 and Europe in 2017 for use against childhood spinal muscular atrophy, a muscle-wasting illness; inotersen, approved in 2018 for hereditary transthyretin-mediated amyloidosis (hattr), which damages the peripheral nervous system; and volanesorsen, approved in Europe in 2019, which lowers levels of triglyceride fats in the blood of people with a metabolic error that makes them far too high.

Ionis currently has a further 37 antisense molecules in clinical trials for conditions including Huntington’s disease (a study being carried out in collaboration with Roche, a large Swiss pharma company); amyotrophic lateral sclerosis, Alzheimer’s disease and Parkinson’s disease (in collaborations with Biogen, a specialist in treatments for neurological disease); beta thalassaemia, a blood disorder similar to sickle-cell anaemia; and cystic fibrosis.

The firm is also developing, in collaboration with Novartis, another Swiss company, a way of reducing levels of lipoprotein(a), a particularly damaging form of low-density-lipoprotein (ldl) cholesterol. Lipoprotein(a) levels are untreatable with existing medicines; Pelacarsen, as the drug is known, is in phase 3 clinical trials to see if it can change that.

Unlike molecules of mrna, which can tolerate only a small amount of chemical tinkering before becoming ribosome-unfriendly, antisense molecules can be tweaked quite a bit, and thus made long-lasting. 

Ionis’s researchers have worked out how to stabilise them so that they will hang around inside cells for months. 

This is important because most of Ionis’s targets are chronic diseases that require continuous treatment. 

The fewer injections per year the better.

While biotech companies were beavering away at antisense molecules in the 1990s, researchers elsewhere discovered that nature had a similar technology of its own: gene silencing, a process guided by small interfering rnas (sirnas). 

The early 2000s saw a gene-silencing biotech boom led by Alnylam, founded in Cambridge, Massachusetts in 2002, and Sirna Therapeutics, which got going in San Francisco the following year.

Established pharma companies, including Abbott, Merck, Novartis, Pfizer, Roche and Takeda, waded in, too, with Merck buying Sirna for more than $1bn in 2006. For almost a decade, attention and money were showered on the field. 

But though there were many promising leads, they failed to turn into drugs. By the early 2010s it seemed that the party was over.

Nonlinear, nonvisual and inclusive

Alnylam, though, kept dancing. In 2014 it bought what was left of Sirna from Merck for a knock-down price. It launched its first product, patisiran, a treatment for hattr, in 2018. 

It now has two others, givosiran and lumasiran, which also address rare genetic disorders.

A fourth substance developed using its technology has broader appeal. 

This is inclisiran, developed to treat an inherited disorder that pushes the concentration of ldl cholesterol in the blood to dangerous levels; around 30m people worldwide suffer from it. 

A firm called the Medicines Company licensed Inclisiran from Alnylam to bring it to market. With approval looking likely (it was given in Europe late last year) Novartis bought the Medicines Company for $9.7bn in January 2020.

According to Akshay Vaishnaw, Alnylam’s head of r&d, the firm has another 14 sirna drugs in clinical trials. 

These including potential treatments for haemophilia, hepatitis B and recurrent kidney stones. 

Arrowhead Pharmaceuticals, of Pasadena, California, has eight potential sirna drugs in trials, including one directed at cystic fibrosis. 

Dicerna Pharmaceuticals, of Lexington, Massachusetts, has three.

These sirnas work by straddling the worlds of shape and sequence. 

Their shape fits them into a group of proteins called an rna-induced silencing complex (risc). 

But a bit of the sirna is left sticking out of this complex; this tail contains a sequence complimentary to that of the rna to be silenced. 

When sirna and mrna meet, the proteins in the risc chop the messenger to pieces. (A conceptually similar mechanism for the rna-guided protein-executed chopping up of genes found in bacteria is the basis of the crispr tools now revolutionising gene editing.)

In plants and invertebrates the natural function of the sirna mechanism is clear: cutting up mrnas associated with viruses. 

They do not seem to serve that function in vertebrates, and no one is quite sure what they do instead. 

But that does not stop them from looking like promising drugs.

So do another set of rnas associated with riscs: micro-rnas, which use their complementary sequences not to destroy mrnas but to regulate them. 

The human genome seems to contain about 2,600 of these mirnas, and they are thought to be involved in regulating the rate at which about 60% of the genes describing proteins get transcribed. 

Several look like promising therapeutic targets.

Since the active bit of an mirna is a single-stranded sequence-specific tail, the obvious way to target them is with antisense. 

Regulus Pharmaceuticals, a firm that started life as a collaboration between Ionis and Alnylam, is trying to develop antisense molecules aimed at mirna-21 to treat two kidney-related genetic conditions in which that mirna plays a role. 

When you start targeting mirnas, though, things get positively baroque. 

Santaris Pharma, a Danish firm, has developed Miravirsen, an antisense suppressor for mirna-122 which the hepatitis C virus uses for its own unhelpful ends. 

The drug has now been taken on by Roche.

The innovation continues. 

Mina Therapeutics, a startup in London, is working on the potential of sarnas, which activate genes which otherwise stay silent. 

Others are investigating systems for “self-amplifying” mrna drugs. 

These mrnas would inveigle a cell’s ribosomes into producing not just the protein that was meant to be delivered, but also a second protein, called rna-replicase, which would make more of the mrna, thus leading to even more protein being expressed. 

There is surely further cleverness to come.

Could be so exciting

Even if only a fraction of these possibilities pan out it looks certain that, in popularity contests to come as in stockmarkets today (see chart), more people will be plumping for rna. 

Their support will be welcomed by the small band of biologists with an interest in the very earliest history of life that has long formed the discerning core of the molecule’s following. 

Life needs both a way of doing things in the now—catalysing the reactions on which its metabolism depends—and of passing information into the future. 

Of the molecules known today only rna, in its shape-and-sequence versatility, can do both those things, dealing with the needs of the everyday at the same time as encoding instructions for its own reproduction in the form of a legible sequence. 

This suggests to many that early life spent some time in an “rna world” before the division of labour allocated doing things to the proteins and storing data to dna, reducing rna to a supporting role in the world it had created.

The application of rna has met many obstacles over past decades, and the fact that it has proved itself in vaccines does not mean it will not meet more in the future. 

But it does seem that medicine now has a way to target drugs not just at proteins, but at the processes that make them, and that opens up new realms of possibility. 

The next rna world awaits. 


By Egon von Greyerz

Instant gratification is what drives the world and especially investment markets.

I often hear complaints that gold is a useless investment since it doesn’t go up fast enough.

We have invested heavily into gold for ourselves and our investors since 2002 when the price was $300.  Since then gold is up just under 6X.

Sure it has not been a straight line and there have been major corrections on the way.


But Bitcoin and Tesla are much more exciting so why should an investor hold gold – an incredibly dull investment for the majority of people.

If I tell investors that it is absolutely critical to hold gold for wealth preservation purposes as the world financial system is the biggest bubble in history, most would ignore or ridicule me.

And if I tell them that the dollar and most currencies are down 97-99% since 1971 against gold and down 85% since 2000, they would yawn. They are only interested in their nominal stock market gains not understanding that they have gained nothing in real terms.

But if I proclaim that gold in 2021 could reach $3,000 some will prick their ears. (More about gold reaching that level, and higher, later in the article.)

Still most people prefer to stay in stocks totally unaware that the majority of stock investors are going to ride the stock market all the way to the bottom. And this time it won’t be a V bottom like March 23, 2020 but an L bottom lasting at least a decade or longer.

Both fundamentally and technically a stock market crash of massive proportions is guaranteed. Whether it starts tomorrow or we first see a final meltup is unimportant. Regardlessly, THE RISK IS GARGANTUAN!


I can hear voices calling me a Cassandra and a doom sayer. For the ones who don’t remember Greek mythology, Cassandra was the daughter of king Priam and was given the gift of prophecy by Apollo. But as Cassandra did not respond to Apollo’s approaches, he gave her a curse that although all her “dark” prophecies were accurate, nobody would believe her.

I am not a Cassandra predicting doom and gloom but just someone who has spent his life analysing and understanding risk.

That’s why for example in 1999 I told my partner in an e-commerce business that we must sell the company at the then ridiculous valuation of 10X sales with no profit. The buyer was a Nasdaq company which went bankrupt a few years later after an acquisition spree paying grossly inflated prices.


Most of the expert tech investors in the late 1990s rode the market all the way down by 80% with many companies going bust.

Risk analysis is also why I wouldn’t buy Bitcoin. Yes, I am aware that a speculative mania could drive it to $1 million. But I am also aware that governments could ban Bitcoin, making it worthless.

So not a good risk in my view.

An equally terrible risk is Tesla.

To buy Tesla at a P/E of over 1,000 and a pie in the sky market cap of $650 billion is as risky as jumping out of the Empire State Building.

If Tesla doesn’t fall by at least 80% in real terms over the next few years, I will eat my hat. Not that I expect to lose that bet, but to get some enjoyment out of the minuscule chance of being wrong, the hat would of course be made of the finest Swiss chocolate!

Remember that an investment can become more overbought than anyone can imagine just like the Nasdaq in 1999-2000. But the subsequent fall is inevitable.


Most people still measure their assets in currencies like dollars, pounds, euros, that are dropping faster than the Niagara Falls.

If you want to know your real stock market gains since 2000, you should deduct 85% since that is the loss of the dollar’s purchasing power in real terms since then.

More than 99% of investors will have lost money on that basis. So maybe they are not so clever after all.

Oh, how wonderful stock market gains are until you realise that it was all an illusion due to governments’ and central banks’ complete screwup of the economy and the currency.

Governments have learnt from master manipulators like Goebbels that you can fool all of the people all of the time. And this is simply because greed and the need for instant gratification stop people looking for the truth.

GOLD – $3,000 NEXT

I have recently received more emails than usual from people that are totally disillusioned with gold. I hasten to add that they are not from our clients who master the art of wealth preservation. This is normally a very good sign that a turn of the gold price is near.

These emails are from investors who are buying gold for instant gratification. Anyone who bought gold in 2000 at $290 is not concerned. But the ones who bought near the top in 2011 around $1,900 have obviously had a long wait.

What makes them more frustrated is seeing stocks going to ridiculous heights whilst they are missing out.


Let me give people who are frustrated with the gold price the reasons why they shouldn’t be:

1.- Firstly, physical gold is not bought for instant gains but as insurance and protection against a rotten financial system and constantly depreciating currencies.

2.- If you buy gold for the right reason, you are buying ounces or kilos of real wealth that should not be measured on a regular basis in a currency which is being debased on a daily basis with unlimited printing of worthless paper money.

3.- Your best friend when it comes to supporting the value of gold is your central banker. Remember that throughout history he has without fail worked diligently to destroy the currency.

4.- Right now we are in the midst of the biggest global money printing exercise in history. Gold has not even started to reflect the total annihilation of paper money.

5.- In relation to US money supply, gold is today at the same level as in 1970 when the gold price was $35 or in 2000 when gold was $290.

6.- Just reflect on the statement in the chart below. In real times gold is now as cheap as in 1970 just before it started to climb 24X from $35 to $850 !!!

7.- And it is as cheap as it was in 2000 before gold climbed almost 7X from $290 to $1,920.

8.- Like most commodities, gold moves in waves or cycles. It is no use worrying about if gold at certain times is manipulated by the BIS (Bank of International Settlement), central banks and bullion banks.

9.-Yes of course there is intervention, these banks admit it themselves. Even Alan Greenspan, Federal Reserve chairman at the time, testifying before the U.S. Congress in 1998 admitted, “central banks stand ready to lease gold in increasing quantities should the price rise.”

10.- We see regular flash crashes in gold at nighttime when the market is dead with the price dropping $30-50 in a few seconds. This is blatant manipulation as nobody would sell big quantities of gold in a market where the buyers are asleep.

11.- As has been reported by many market observers like Alasdair Macleod, there are major shortages of gold and silver on the London market.

12.- To alleviate this the BIS is issuing gold swaps to the bullion banks so that they with paper gold can make up the major physical short falls. I have regularly reported the massive turnover of paper gold on the London market. The daily LBMA trading is 2X the S&P trading.

13.- This frenetic juggling of paper gold by the BIS is clearly a desperate attempt to cover up major shortages in the physical market. Why else would gross trading volumes be 2X greater than the S&P 500 which is a much bigger investment market.

14.- Like all manipulation the chicanery in the paper gold and silver markets will eventually fail spectacularly.

15.- As Matt Piepenburg and I have covered in many articles, inflation is likely to surge in coming years and so will interest rates. But just like in the 1970s, real inflation will be running ahead of interest rates, creating negative real yields which is very beneficial for gold. As I mentioned above, it was in that climate that gold went up 24X.

16.- The correction we have just seen in gold was a natural part of the cyclical move of any commodity. For the last few weeks, I pointed out that gold would go down to the low $1,700s and probably overshoot on the downside as is often the case. Well, that is exactly what happened and the correction is now over. Still, it is important to understand that an unlikely attempt at around $1,670 again would not change the very bullish picture for gold.

17.- The coming upmove in gold will be extremely strong and take everyone by surprise. There will be no reason for a major correction before the $3,000 level.

18.- Whether gold will go to my long standing target of $10,000 IN TODAY’S MONEY or reach Jim Sinclair’s target of $50,000, we will see in the next 5 years. Also likely are probably hyperinflationary levels of $100 million or $100 trillion.

19.- The levels above are neither forecasts nor meant to be sensational projections for attention seeking. No, they are likely consequences of all the factors that I have outlined above.

20.- Exponential deficit and debt growth combined with galloping money printing will inevitably destroy most paper currencies in coming years.

21.- The major structural shortages of physical gold and a failure of the gold paper markets could make physical gold unavailable at any price.

22.- What I say about gold above will be even more relevant for silver which is likely to go up 3-5X as fast as gold. But remember that silver is not for the fainthearted since it is considerably more volatile than gold.

23.- In the coming bear market for currencies and bull market for precious metals, gold and silver will not just maintain purchasing power but massively outperform and become the must have investment.

24.- But above all, do not buy gold and silver for speculative purposes. Gold and silver is your insurance against the coming end of a monetary era when all currencies and bubble assets will implode.

25.- You can today buy this insurance of gold and silver at a ridiculously low price. Don’t wait. Soon this insurance might not be available at any price.

Paradise Lost


So a single political party gains control of a lockdown-battered country desperate for any and all forms of government spending. 

Direct payments, loan forgiveness, infrastructure, all of these and more are not just possible, but popular. 

The president and his Congressional allies simply write the bills, pass them, and bask in the near-universal admiration of their generosity. 

In fact, the only real criticism comes from their own party’s left wing, which demands even higher spending, bigger deficits, and faster money printing. It’s like being a kid in a candy store. 


But then – only a couple of months in — headlines like these began to appear:

Economy Adds Over 900,000 Jobs Beating the Consensus By a Mile

Manufacturing boom brings more signs that inflation is building rapidly

US Dollar’s Status as Dominant “Global Reserve Currency” Drops to 25-Year Low

Investors see higher interest rates as the biggest threat to stocks, expect 10-year yield to hit 2%

US New Vehicle Sales for March Smashed Expectations

Suddenly, the flat-on-its-back, credit-starved country looks like an overinflated bubble in need of restraint. 

As Politico explains the resulting dilemma:

Biden’s spending plans collide with a resurgent U.S. economy

President Joe Biden is pitching his $2 trillion infrastructure proposal as the “largest American jobs investment since World War Two,” a plan that will put millions of people back to work as the country emerges from the coronavirus crisis.

The economy, meanwhile, is showing signs of recovering on its own.

More than 916,000 Americans returned to work in March, the Labor Department reported on Friday, far surpassing consensus expectations and marking the biggest jump in employment since the summer as Americans get vaccinated and more states and cities allow businesses to reopen. 

The overall unemployment rate ticked down to 6 percent.

It’s the latest in a series of reports this week showing a resurgent economy, with consumer confidence jumping to levels not seen since the start of the pandemic and manufacturing activity surging to its highest peak in nearly four decades. 

The S&P 500 also closed the week at a record high. Together, the numbers signal the U.S. is well on its way toward a revival, one that’s widely expected to reach record levels of growth later this year.

And that in turn has blunted one of the central pillars of the Biden administration’s argument as to why the sprawling infrastructure plan is so sorely needed, even after $1.9 trillion in relief money passed just last month — that “it’s about jobs,” as White House press secretary Jen Psaki put it this week, and “the first part of his plan toward recovery.”

What happens now? 

Obviously, the US government will continue its spending spree because, damn it, that’s why it’s there. 

And also because … injustice! 

Millions of destitute former students need their loans forgiven. 

State and city pension plans have to be saved from their own mismanagement. 

Russia, China, and Iran have to be humbled. 

The infrastructure plan, meanwhile, has already been announced, so it has to be funded.

And yet… Americans are already combining their stimmy checks with the money they’re saving by not paying rent, and they’re buying stuff. 

Companies are hiring people to make said stuff. 

Inflation is rising as surging demand causes shortages. 

And interest rates are spiking in response. 

Let these trends continue and the candy store will close, forcing today’s expansive, inclusive, simulative government to become the one thing it never expected to be, a Scrooge bent on restraining overexuberant growth. 

As the old saying goes, “If you want to make God laugh, tell Him your plans.”

Fun story so far, right? 

But it’s actually a lot more ominous than it sounds, because the current wildly-overleveraged system can’t tolerate rising interest rates. 

But suppressing rates with trillions of newly-created dollars will turbo-charge the inflation that is pushing interest rates up. 

Which makes this a problem that can’t be fixed and, at least potentially, the end of a 70-year era in which more debt and easier money could always be counted on to save the day.

Americans have saved a lot of cash, and they are ready to spend it.

By Ben Casselman

Shoppers at a Bed, Bath & Beyond last month. With the vaccine rollout accelerating, economists expect Americans to start spending again.Credit...Mark Lennihan/Associated Press

Economists think the big job gains reported on Friday are just the beginning. 

One reason:  U.S. households had $2.4 trillion in savings in February, $1 trillion more than a year earlier. And that was before the latest wave of $1,400 relief checks started going out in March.

The primary factor holding back spending has been the pandemic, which has prevented people from spending on restaurant meals, vacations and concert tickets. 

But with the vaccine rollout accelerating, that could soon change.

About 35 percent of Americans plan to spend more on travel over the next 12 months than they do in a typical year, according to a survey conducted last month for The New York Times by the online research firm SurveyMonkey. 

About 28 percent plan to spend more than usual at restaurants. 

And over all, close to 70 percent of adults plan to spend more than usual in at least one category, at least if the health situation allows.

“They have the money in the bank, they’re ready to spend it, but what was holding them back was not having a comfort about being able to go out,” said Jay Bryson, chief economist for Wells Fargo. 

“We’re getting into a critical mass of people that are feeling comfortable beginning to go out again.”

But there are signs that Americans remain cautious. 

The survey was conducted in mid-March, just as the Treasury was preparing to send the $1,400 checks to millions of households. 

More than half the survey respondents who expected to receive checks said they planned to save most of the money or pay down debt. 

One-third said they would use it for immediate needs like food or rent. 

Only 10 percent said they planned to spend most of the money on discretionary items.

And while many Americans may be dreaming up ways to spend the money they saved during the pandemic, those hardest hit by the crisis are still trying to regain their financial footing. 

Among the unemployed, 62 percent said they planned to use their stimulus check to meet immediate needs, compared with 29 percent of the employed. 

Only 3 percent of the unemployed said they planned to use their stimulus checks on discretionary purchases.