Chemically Programmable Immunity

The History of Disease

Early stages in major advancements are never heralded or even noticed. It is years or decades before things that will dominate a field are obvious to careful observers. Successful investors are lucky or prescient.

Altermune is a distinct change in direction for the medical treatment of microbial infections, metabolic disorders, cancer, any number of problems where surgical procedures are too crude, present chemical interventions are losing out to resistant strains, and yet some kind of molecular intervention is necessary and still makes sense.

The vertebrate immune system was evolved to deal with molecular and organismal problems. Most of what kills us is too tiny for us to notice with our unaided eyes. Cell to cell combat, molecule to molecule interactions are where we live or die in this epoch. Big animals, even humans, are not our problem.

Our immune system has been performing remarkably while our population has grown immensely and the mathematics of infectious disease alone ignoring for the time being cancer and metabolic disorders associated with an abundance of unhealthy food does not favor numerically successful species.

This is reasonable, for biology is exquisitely balanced. But I don't care to see my offspring come to an untimely end before my eyes. Infectious disease is therefore something I think about.

In 1917-1918, influenza brought down a particular mixture, not the infants or the very old, but the young and the strong. We don't know exactly why. We can speculate about immunities, but it becomes obvious rather quickly that we don't know why. Next time it may be the same or it may be the opposite.

Humans have this system of immunity, which recognizes novel structures, possible problems, in our fluids. We are standing creatures with brains and arms, not formless pools of microbial mush, because of that system. It has kept us intact in spite of our distinct resemblance to universal food. But our immune system is overworked. Too many of us are passing too many things around and the planet has virtually shrunk to the size of a 747's daily range.

We have immensely increased the rate at which our immune system has to deal with new things. Perhaps just by luck or was it destiny, we are now in possession of things like nuclear magnetic resonance spectroscopy, electron microscopes, sequencers of proteins and nucleic acids, chemical reagents of dazzling complexity and the multitude of us now becomes an advantage. There are lots of chemists in the world. We communicate electronically at the speed of light using satellites; we are a force to be reckoned with.

We have been slowly developing chemistry, the art of dealing, using instruments we devise, with things that are much too small for us to see. They have plus and minus charges on them that we can't feel; they have oily places on them much too tiny for us to notice oil and they have water-loving patches too small for us to see oil droplets beading up on the water. Microbes need all of these things, specific types of them, in fact, to survive, and none of them are beyond the scope of our instruments and our synthetic tools. That's our advantage. Just in this last century we have come to know these things the way we used to know javelins and swords.

How can we help our immune system?

Altermune has a shot at it.

Give its antibodies, its workhorse molecules, bionic arms, little chemical extensions that allow an old antibody to do new tricks. Altermune, LLC, in collaboration with Ron Cook of Biosearch in Novato, CA, re-directed antibodies whose job used to be binding to something called the alpha-Gal epitope or galactose-alpha-1,3-galactosyl-beta-1,4-N-acetyl glucosamine, to influenza using DNA aptamers attached to the alpha-Gal epitope. These linkers can tightly seize an influenza virion, and turn it over to a hungry human macrophage. The change was accomplished with a drug which can be inhaled. The virus never saw it coming.

What else can we do with this system besides cure the flu? There are bacteria like the famous E. coli out there that have learned how to outwit our cherished antibiotics. We need to deal with them, and resistant strains of Staphylococcus aureus, that can rot you away in front of your doctors and family in the finest hospitals in America. And no surprise, other resistant bacteria are on the rise. Resistance to antibiotics was already in the world when Alexander Fleming discovered penicillin England in 1929. His advisor, Almroth Wright, predicted antibiotic resistance before it was even noticed experimentally. After all, Fleming had only borrowed penicillin from a mold, which had been using it to kill bacteria for at least a hundred million years. Some bacteria had come up with an antidote, penicillinase, which in 1929 no one knew was coded on a plasmid that could be transferred from bacterium to bacterium as needed. But, it only took about fifty years before the enzyme was transferred to a bacterium with a taste for warm blood.

The story is about the same for all of our antibiotics.

We need to make our own from first principles, new compounds that have never been seen on this planet. The Altermune method, taking advantage of the evolutionary skill of our immune system for killing micro-organisms once their structure has identified them as being enemies, is developing the process of building bionic arms for antibodies, which once the offending microorganism is identified, can grab it. The process already is quick and efficient, and shockingly so for the microbes, who are used to the slow creep of biology, and know nothing of nuclear magnetic resonance or high resolution mass spectroscopy.

About Altermune

An example of a linker between a pathogen and antibodies to the alpha-Gal epitope

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Interview with Julia Puppe

Special Report

Groundbreaking discoveries of the past and the future

Julia Puppe spoke with Nobel Prize winner Kary Mullis about PCR and a potential antibiotic for the flu.

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Mullis likes a challenge. The harder it is for him to understand a phenomenon immediately, the more interesting it is. "You look at something and ask yourself: "Why is this that way?" In order to figure that out you need to read everything other scientists have said about it. This requires you to learn a whole new language." Over the last 10 years, Mullis got interested in immunology and learned the language immunologists speak. "I had an idea about how to tackle infectious diseases. When a new pathogen enters your body, the reaction is a new immune response. However, it can take a month before your immune system is really up and running. During that process a fast pathogen can wipe you out. So I thought: "Why not use an old immune response, just refit it?". But in order to even start to do something about it, I had to learn the language of immunology."

Mullis' language skills developed and so did his idea. This led to the formation of his latest venture, Altermune LLC, and his most recent patent application, which covers an approach for instantly mobilizing the immune system to neutralize invading pathogens and toxins. "We are altering the target of an immune response by using specific synthetic chemical linkers that divert an immune response from its nominal target to something completely different, which you would right now like to be temporarily immune to," explains Mullis and gives an example: "Let's say you just got exposed to a new strain of the flu. You're already immune to alpha-1,3-galactosyl-galactose bonds. All humans are. Why not divert a fraction of those antibodies to the influenza strain you just picked up? A chemical linker synthesized with an alpha-1,3-gal-gal bond on one end and a DNA aptamer devised to bind specifically to the strain of influenza you have on the other end, will link anti-alpha-Gal antibodies to the influenza virus and presto, you have fooled your immune system into attacking the new virus."

Sounds simple enough, but developing this chemical linker is not. "Doing this is a lot harder than I envisioned it when I first thought about it. There are a lot of people involved unlike PCR, where I could do it myself," sighs Mullis. With his team of organic chemists, influenza and poultry specialists and immunologists, he is currently testing the Altermune method in chickens against a strain of flu called H3N2. Most humans are already immune to this typical laboratory strain, but Mullis' vision includes H5N1, which is likely to prove disastrous. "The flu has been living with humans for a long time. And it looks like about every once or twice every century, there is an epidemic. If there is going to be a worldwide epidemic of H5N1, it's just a matter of time - and this time is likely to be worse than last time," is Mullis' grim prediction ...