New Antibiotics Revealed In Humble Soil
This week we’re taking a break from commenting extensively on the market’s gyrations, and looking a little more long-term at some new developments in biotechnology.
What Really Boosts the Longevity of Human Populations?
Some cutting edge biosciences, such as novel cancer therapies, get a lot of attention from investors, including us. However, the real drivers of health and longevity over the past century have been more humble: better nutrition, better sanitation, and perhaps most important, the discovery of antibiotics.
In many ways, as far as longevity and quality of life go, agriculture was a big step down for our ancestors. While cereal crops could support a larger population and allow them to reach reproductive age, the drab and monotonous diet of gruel that most peasants ate throughout history did not give them the constitution to fight off disease. New diseases also arose and spread rapidly once people were concentrated in towns and cities — and many of these diseases were mutant species which originated in domestic animals and found a way to jump to human hosts. It wasn’t until the 1800s that human life expectancy among “civilized” people again reached the level of our paleolithic hunter-gatherer forebears.
The tide began to turn as the industrial revolution allowed cities and towns to improve their sanitation, reducing the disease burden in their populations. Agricultural innovations, such as the Haber process for making fertilizer from natural gas, allowed for more abundant food production and a more well-nourished population — whose immune systems were more robust and better able to fight off infectious disease.
However, it wasn’t until 1928 that humans got a tool to use in their fight against infectious bacteria and the diseases they cause. Scottish microbiologist Alexander Fleming noticed that a colony of bacteria he’d been growing in a petri dish had been killed by a fungal infection; this marked the discovery of the first antibiotic, penicillin. Fleming and his colleagues won the Nobel Prize for the discovery in 1945.
Penicillin, though, was just the first. Many more antibiotics were discovered by a Rutgers University team led by Dr Selman Waksman, who won a Nobel for his work in 1952. Waksman’s scientific career started in soil microbiology. With his discovery of streptomycin-producing micro-organisms in a soil sample, humanity had at long last a cure for tuberculosis.
Selman Waksman’s Soil Discoveries Cured Tuberculosis
The Real Source of Antibiotics
Humans are a little arrogant when they credit themselves for “creating” antibiotics. It’s a bit like those who credit Christopher Columbus or Leif Eriksson with “discovering” a North America that was in fact already inhabited by millions of people. There are a lot of critters on the planet with an interest in fighting infectious bacteria — and most of them are other bacteria. The antibiotics humans have discovered are really chemical weapons evolved over billions of years in an ongoing microscopic struggle for survival in the earth’s soil and water. The antibiotics such as penicillin and streptomycin that pioneers like Fleming and Waksman were able to find, were lucky hits — fortunate discoveries from a vast, teeming, and almost totally unknown microbiological world.
Virtually all of the discoveries of new antibiotics since have also come from soil and water microbiology. The basic process involves identifying organisms in soil and water samples, and then “culturing” them — growing them in a laboratory — and seeing if they express proteins that could be used as antibiotics. The problem is that until recently, techniques of identifying and isolating soil micro-organisms reached a plateau — everything that was going to be found through Waksman’s methods had already been found.
At the same time, the over-use of antibiotics in human populations and in livestock created antibiotic-resistant strains, with an ever-dwindling stock of new, effective antibiotics to combat them. Over the past decade in particular you have probably read a lot of alarming stories in media about antibiotic-resistant bacteria stalking hospital wards. We have one young friend who got such an infection while in the hospital and was told by his doctor “Either you’ll get better or you’ll die” — not something that developed-world folks schooled in the omnipotence of medicine are used to hearing.
It’s also important to recognize that effective antibiotics don’t just cure infectious diseases — they have also enabled wonders of modern surgical techniques. Without effective antibiotics, most advanced surgical interventions would be unthinkable.
Even though the need for new antibiotics has become so great, biopharmaceutical firms have been reluctant to sink big research and development budgets in order to meet this need. This is in part because any novel antibiotic is treated by physicians with great reserve — they want to save it to use as an absolute last resort, because they know that the more it’s used, the quicker the bugs will evolve resistance to it. That kind of parsimony is not what a drug company looks for when it is contemplating spending one or two billion dollars on a research program.
What has been needed are a new platform for discovery and a rich new source of hitherto unknown micro-organisms that might produce valuable and novel antibiotics. Thanks to cheap gene sequencing technology, that need is beginning to be met by a field called “metagenomics.”
Metagenomics To the Rescue
Waksman’s techniques allowed the isolation and culturing of a few soil and water micro-organisms. However, a field called “metagenomics,” pioneered in the 1990s by scientists such as Dr Sean Brady of Rockefeller University, has revealed that we have only identified a tiny fraction of all the micro-organisms that exist in the world’s water and soil. If you think that a distant rainforest may be the source of transformative medicine from unknown plant species, metagenomics shows that such transformative medicines could come from unknown micro-organisms in your own backyard dirt.
The New Secret Weapon Against Superbugs: Your Dirt
Metagenomics, rather than trying to isolate and culture specific micro-organisms, uses high-throughput genomic analysis to break up and examine all the genetic material from all the organisms present in a sample. When this first started to be done, scientists saw lots of unexpected genetic material — eventually allowing them to infer the presence of large numbers of otherwise unknown organisms.
(Incidentally, to us, this discovery is a powerful argument in favor of agricultural techniques that respect the microbiome, as opposed to extractive industrial techniques that essentially “strip mine” the soil and attempt to replenish it with a few simple chemical inputs.)
Uncovering New Antibiotics
With the advent of modern genetic analysis and manipulation, and massive parallel processing by powerful computers, scientists can comb through all the genetic material they find in a sample and locate sequences of DNA that look promising — and then insert that DNA into a micro-organism that can be easily cultured. In this way, scientists can now explore a vast new spectrum of bacteria-fighting organisms… and borrow their hard-won evolutionary “know how” to produce novel antibiotics for humans.
Our exploration of this topic was sparked by a paper that Sean Brady recently published in Nature Microbiology: “Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens.” Interested readers can access the full article here.
In brief, Dr Brady’s team was able to take a soil sample from his parents’ yard in the southwest and discover genetic material that produces a new class of antibiotics called “malacidins.” He notes:
“The malacidins are broadly active against Gram-positive bacteria including multidrug-resistant pathogens and bacteria resistant to mechanistically diverse, clinically used antibiotics… Our experimental efforts to induce resistance to malacidin in the laboratory have so far been unsuccessful.”
That is, metagenomics has borne some of its earliest fruits — a new potential class of antibiotics effective against resistant strains of bacteria, with a novel mechanism of action, against which its targets have not rapidly developed resistance.
While we may still be years from commercialization of malacidins, or of any new discoveries made available through this process, the discovery suggests to us that we may soon turn a corner in the development of new antibiotics.
Investment implications: In order to spot emerging opportunities early, investors should be aware of cutting-edge technological developments, particularly in biotechnology. Metagenomics is one of these developments. Dr Selman Waksman’s discoveries generated large profits for the companies that licensed those discoveries in the 1950s and 1960s (and he used his proceeds to endow Rutgers’ Waksman Institute of Microbiology). When we identify a scientist such as Dr Sean Brady, we usually keep watch so that we are aware of private companies that they found or for whom they consult. When those companies come public, an investor who already has knowledge of the significance of the underlying science can benefit. We also watch for other scientists and other institutions pursuing the same lines of research.