We are all chemical engines. So, what exactly is a chemical? Chemicals are anything that occupies space in the universe and exist in either a solid, liquid, or gas form – matter! Chemicals within living organisms are considered biochemicals and are organized into chemical networks (an integrated chemical process that establishes life and the maintenance of homeostasis). Homeostasis is simply a scientific term that means maintenance of the status quo. So, a healthy living organism must respond to its environment and manage different threats. The systems that are designed to ensure that the cell remains healthy are called homeostasis. Drugs are also chemicals. Drugs enter an organism and make their way through biological systems to interact with many chemicals. Sometimes those interactions lead to changes in the chemicals with which the drugs interact, altering one’s physiology or psychology. One must have a keen understanding of basic scientific terminology, these chemical networks, and biological systems to create drugs and use them to make a difference in all patient populations. Ready? Let’s get started.

Welcome to the n-lorem podcast series. Since I

found it n-lorem, I've been involved in many discussions

focused on these patients and creating both short and long

term solutions to meet the needs of these patients. And I've been

deeply touched and impressed by the number and diversity of the

people involved, the energy, the progress and the commitment of

so many people. It involves many academic scientists and

physicians, charitable foundations, parents and

patients who are involved. So it really is a very diverse group.

I've been particularly impressed with the patients and parents,

most of whom have really no basic training in the chemical

or biological sciences or medicine, and yet have mastered

at least parts of the science and the medicine and achieve

really quite remarkable steps. And I think those people are to

be especially applauded for their their willingness to

commit in their ability to learn what in fact, takes most of us

many years of training. I've also been pressed by several

notable absences. I've not encountered a single person with

any real knowledge or experience in drug discovery and

development. And since that's what we are discussing for these

patients, that's a critical deficiency. And that is

certainly one of the voids that I hope to fill with the series

of podcasts that are more lecture like. So given the

diversity of those involved in addressing the needs of ultra

rare patients, I think there may be some real value in briefly

going from the absolutely most basic concepts to what drugs

are, what they can and cannot do, and how they come to be. I

think this will help assure that we all are coming from the same

starting line, and that we are all using are able to use a

shared vocabulary. I'm confident that all of you understand some

of this and some of you probably understand all of it, and some

of you may understand it better than I do. But even for those

who are fully informed, I think it is sometimes value to hear

the basics from a different perspective. And I hope to give

that to you. We will begin with the absolute simplest of ideas

that I promise I will quickly enroll you in a masterclass in

what is going to be necessary to broadly enhance the treatment of

patients with ultra rare disease. Let's begin with this

seemingly so simple statement. All drugs are chemicals. And

that is true whether you take a prescription medicine, and over

the counter medicine, or a mixture of natural products or

supplements that you get at a natural food store. Drugs differ

from other chemicals only because they are administered to

humans or other animals for therapeutic purposes. And by

therapeutic purpose, we mean that we want to alter the state

of the biological systems that result in characteristics that

we see in patients or set another way we plan to alter the

phenotype of the patient, we plan to convert the disease

phenotype the patient to a healthier phenotype, which

brings me to the word phenotype. A phenotype is a composite set

of characteristics that a biological system, in this case,

it's a patient, displays at a particular moment, the phenotype

of a patient comes to be as a result of the genetic

characteristics of the patient, the effects of current

environments, and the history of the patient. So the phenotype of

a patient today reflects all the experiences the patient has had,

and all the previous phenotypes expressed. And the next

phenotype that will be expressed for that patient will be a

consequence of the phenotype that we begin with before we add

a drug. And then of course, the addition of a drug. A genotype

is the sum total of genetic information patient has, you can

think of it as the total genetic capability possible for that

patient from which that patient selects those traits that are

expressed to create the phenotype that's displayed when

the patient comes into our office. The genotype is a

product of the genetic information that the patient

inherited from his parents, including all the mutations his

or her parents had, and any mutations that have happened to

the genes of the patient during his life. Almost all drugs, and

we'll talk about this extensively, are designed to

alter the phenotype of the patient, but not the genotype.

On the other hand, when we engage in gene therapy, we're

altering the genotype so that a healthier phenotype will be

expressed in the ANA cancer group. Dogs are designed or the

genotype of cancer cells and CRISPR and gene therapy are ways

to alter the genotype as well. So first key point or a key

point, drugs are administered to alter the phenotype of patients

into healthier phenotypes. Most drugs are designed to alter the

phenotype without affecting the genotype. And in fact, we work

very, very hard to avoid genomic effects because it can often be

very toxic. And of course, they last for a lifetime. Gene

therapy and CRISPR are ways to create healthier phenotypes by

altering the genotype. Okay, so let's back up to even something

even simpler, chemicals. So what is a chemical? What do chemicals

actually do? And how do biochemicals differ from other

chemicals? Our world is made up of molecules that we call

chemicals. Each chemical has a unique set of characteristics

that establish a unique chemical fingerprint, chemicals vary in

size. And the size of a chemical is measured in units that are

called Dalton's, abbreviated with a big D, because Dalton was

a scientist size can vary from one Dalton to many millions of

Dalton's. Chemicals can be positively or negatively

charged, or they can have no net charge at all, they can be

neutral. Of course, we then have all kinds of drugs that have

different charges as well. Charge density is the pattern of

charge over the surface of a chemical. Chemicals can be water

soluble, and scientists refer to that as hydro – water, philic –

liking water liking, or soluble and fat or lipids. And

scientists refer to that as lipo, fat philic. Liking fat,

like some chemicals are called amphipathic. Those chemicals

dissolve in both water and lipids. And if you were to have

a test tube with water and oil in it, and you shook it up, the

amphipathic chemicals would be found at the interface between

water and the oil. So all of those characteristics and many

more that I haven't gone into form a composite set of

characteristics for that chemical, and it creates a three

dimensional pattern for that chemical. The three dimensional

pattern for each chemical is different is unique to that

chemical, every nanosecond chemicals engage in a myriad of

pattern recognition events with other chemicals. These pattern

recognition events begin with a collision between two chemicals

or more. The frequency of collisions between two chemicals

is a function of the concentrations or the number of

molecules per unit volume of each of the chemicals. So when

two chemicals collide, and they have appropriate three

dimensional patterns, then they can produce a chemical reaction.

In a chemical reaction, the two chemicals that began the

reaction are changed, and they become what's called products.

Chemical reaction then, is a critical component of life. So

this brings us to another key point. Each chemical has a three

dimensional unique pattern. Chemical reactions begin with

the collision between two or more chemicals. Thus all

chemical reactions are concentration dependent; drugs

or chemicals. So the effects of drugs must be concentration

dependent and they certainly are. We often adjust the

concentration of a drug in a patient or animal by adjusting

the dose, and we adjust the dose to adjust the concentration to

that which we want to produce the specific effects. Some

chemicals are essential for life and create biological systems.

And we call those chemicals bio chemicals, but they're really

just chemicals that we find interesting because they result

in who and what we are. Okay. A biological system is a set of

networks of chemicals and chemical reactions that result

in biological behavior. All animals are of course comprised

of cells. Of course, you know that, but have you ever asked

why evolution bothered creating cells? Well, it's pretty simple.

You can think of cells as tiny bags water in which the

chemicals required for life are concentrated sufficiently to

support biological activity. So cells are a means to concentrate

the chemicals you need in a way that allows them to produce

chemical reactions that support life. Our cells are protected

from the environment by a very complex, constantly changing

barrier. That's called the plasma membrane. It's composed

of fats or lipids, and sometimes and some lipids that have a

negatively charged phosphate. They're called phospho, lipids

and then various proteins are integrated in and out of that

plasma membrane. So the next key point cells concentrate the

concentration of chemicals, so that biochemical reactions can

be put induced that lead to life cells perform several functions.

They integrate all the chemicals and the chemical reactions into

complex networks that create then the phenotype of that cell.

Or in the case of a patient, the phenotype of that patient, they

constantly sense and respond to the environment by adjusting

their phenotypes. They are then integrated with other cells of

various types to create organs, and each organ has its own

general set of functions. And they come together to create us

to allow us to manage our life, the organs and fluids of the

body are integrated then into an even more complex set of

networks that are organized in a hierarchical way. And out of all

those sets of chemicals and chemical interactions is created

a composite set of behaviors. And that's the patient we see.

That's the patient's phenotype. And, of course, the phenotype of

anyone or any cell animal person, patient of various, you

know, second by second, depending on how he's responding

to the environment. Finally, most cells also have to

replicate in an orderly way. So they play cells that die of the

same type. And so they have to have a process and allows them

to make new cells or daughter cells, brings us to the next key

point, you and I are simply incredibly complex networks of

biochemicals about chemical reactions that create the

phenotype that we recognize, when we look at ourselves in the

mirror. Many important biological chemicals are in fact

polymers. Polymer, of course, means many units poly many units

mer. One important type of polymer is proteins. The

building blocks of proteins are called amino acids. And for

simplicity, you can think of each of those building blocks or

amino acids as being about 100 Daltons. Pretty small. But when

they're strung together, as polymers, they become proteins.

And they can become very, very large. Typically, we think of a

protein is ranging, say, from 10,000 Dalton's to hundreds of

1000s, and sometimes millions of Daltons. And so you can imagine

how big those molecules are, they've taken literally 1000s

and 1000s of amino acids and put them together sometimes you can

imagine then how complex the three dimensional pattern of a

protein must be. And that's going to be an important thing

to remember as we go forward. Another important set of

polymers are nucleic acids, the building blocks of nucleic acids

are called nucleotides. And you can think of them as being about

300 Dalton's in size, larger than an amino acid, but still

pretty small. These building blocks are strung together

through negatively charged phosphate groups. And since

phosphates are negatively charged, these molecules behave

as acids. That is, if you apply a electrical field to a solution

of nucleic acids, they migrate toward the positive pole. And

that's why they're called nucleic acids. Now, there are

two nucleic acids that matter. DNA is a giant polymer made up

of millions, many millions of nucleotides, and RNA is the

other nucleic acid, polymer. And most RNAs are typically 1000s of

nucleotides in size. So now let's go back to cells, cells

are organized like modern corporations, each cell has a

set of employees that do the work in the cell. For our

purposes, you can think of the working molecules as proteins,

these are the workers there in you know, the shop actually

making the products. The polymers then that we think of

this proteins are made up of amino acids. Now there are only

basic amino acids. So you can think of proteins as using the

language of amino acids. And the amino acid language is pretty

darn complex. It's almost as complex as English in which we

use 26 letters. The information management system of the cell is

quite different. It's comprised of polymers we call nucleic

acid, DNA and RNA. And of course, you know that the

nucleic acid language is much simpler. It just has four

letters A, T, or U, C, and G. And you know, that set of

letters is used in both DNA and in RNA. So this is a vastly,

vastly simpler language than the language of amino acids or

proteins. You can think of it as almost as simple as the Morse

code. And, as I mentioned, the DNA in your cell is just almost

unbelievably large. It said that if you stretch the DNA in a

single cell, single one cell out fully, it would be several

meters long. Now, DNA is used to store genetic information and

the information encoded in your DNA is your genotype. Because

the DNA in every cell is so large, the file has to be

compressed. And it's compressed into structures called

chromatin. And during cell division, they get them sorted

out into different things called chromosomes. Humans have 23

chromosomes, that information in the DNA has to be stored and

protected at all costs. I mean, this is who you are, and you

need to protect it yourself. And so you and I, and all the rest

of us have just a remarkable set of very complex systems that are

designed to protect our DNA, and to repair damage. Now, damage

can happen, because we encounter very reactive chemicals that can

damage DNA, many of them are just the products of life, just

the biochemical reactions we do, and then others you can

encounter in your environment. For example, if you go to the

beach and sit in the sun and have UV light. A change in a DNA

that isn't corrected by one of those systems, is permanent,

that's called a mutation, you tend to think of mutations is

all bad, that's not true. There are many mutations that can be

beneficial to the cell. And if there is a mutation that's

beneficial to that cell, that cell then will outgrow the other

cells that don't have it, you'll end up with a bias batch of

cells that we would call a clone. The other way mutations

can happen is when the genetic information is copied. And you

can think of these mutations as really just typographical

mistakes, and you make a copy of DNA, when you're getting ready

to make a new cell, you also make partial copies of a lot of

your different parts of your DNA when you need to express a

specific phenotype. So it is an error prone system, it just is.

And so once again, you have a lot of systems in place that

follow the typewriter and correct the mistakes that are

made, mistakes that are corrected, become mutations. So,

how is the information in DNA using course you know this, but

I'll just walk through this very quickly. When it's time to use

the information in a particular gene, that information is

converted to RNA. And if it's an RNA designed to make a protein

that's called messenger RNA. And RNA uses exactly the basically

the same four letter code that DNA does. So that process is

transcription. That's exactly what it is, you're transcribing

a part of the information in your DNA. Now, if the

information in the RNA is to be used to make a protein, then the

nucleic acid language has to be converted to the much, much more

complex language of proteins, the amino acid language. And so

that process is called translation. And that's exactly

what's happening. And yourself, you're taking this information

in one language, the Morse code of your genetics and converting

it to the English of your proteins. Translation. The

reasons these words are used by scientists, is that's exactly

what they mean. So polymers, key points are critically important

for biological systems, each cell stores genotype information

carefully. And when it needs to use some of that information.

And RNA molecule is made. When that RNA is made, that's called

transcription. And then if that RNA is to be used to make

protein information has to be translated in your cell to make

the specific protein. Now, drugs are used to alter biological

systems. Let me just say that, again, drugs are used to alter

biological system. Yes, it is conceptually possible today, I

suppose that we could synthesize a new gene, and that could then

generate new biology. But in most cases, today's drugs are

used to alter biological systems, they don't create new

biology. They alter the biology that you are practicing before

when you take the drug. And so the other way to think of the

drugs is it alters the composite set of characteristics that are

a product of all these gazillion networks in the body to generate

a new composite set of characteristics. Or said another

way, drugs are used to alter a phenotype that we think of as

diseased into a new phenotype that we think of as healthier.

So I want to slow here just a minute and make a point that I

think is far too often overlooked. Even if a drug were

perfectly specific, and there is no such thing. And by that, I

mean that we have, we're using that drug for one specific

desired effect, and it does absolutely nothing else in the

body than just that, even if it's that specific and there has

never been a drug that specific. Even that perfect drug will

alter the composite of all those networks in ways that at the

present time, are still unpredictable. So there's no

free ride with any drug, even a perfect drug produces a myriad

of changes in phenotype that are not today, predictable. Equally

important is the fact that the networks that create a specific

phenotypes, let's say a diseased patient, are unique to that

patient. And they create a biological environment with

which that drug interacts. And so that means that the effects

of drugs are often very different in patients with

diseases compared to healthy patients, and the severity of

disease also can change the effects of the drug remarkably,

and so I just can't emphasize enough how tremendously

important these concepts are, as we think about how to help

patients with ultra rare disease, they can't be ignored.

Yes, when you give a specific drug or chemical or agent,

you're giving it to do a particular job, that its effects

will be defined by all its properties, and the nature of

the person who takes it. This becomes particularly important

in gene therapy. Because of course, with gene therapy, we

are trying to result in a permanent change in the genome,

which could mean a permanent change in all the phenotypes.

And so that would be great if you get only what you want. But

what happens if you get what you want, plus a whole bunch of

other things. So in sum, then, biological systems generate a

phenotype by integrating an incredibly complex array of

chemical reactions into progressively more complex

networks. These networks determine the phenotype that one

presents at a particular moment, phenotypes change constantly or

in response to the environment. And when we administer a drug,

we administer a drug into a biological system. And, and the

effects of the drug can vary as a function of the nature of that

biological system. We see very different effects sometimes in

patients who are diseased and we constantly worry about how the

effects of a drug may change as the patient progresses in their

disease. important concepts to think about. In the next podcast

will now take another step in complexity, and begin to think

about drugs in much more detail.

n-lorem is a nonprofit committed to discovering and

providing personalized experimental treatments for free

for life to patients with genetic diseases that affect one

to 30 patients worldwide, referred to by n-lorem as nano

rare. Many of these patients progress and die without ever

achieving a diagnosis. This is where n-lorem comes in. They do

the impossible by providing hope, and for those that they

can help, free lifetime treatment. For more information

about n-lorem or today's episode, visit nlorem.org any

questions can be sent into podcast@nlorem.org search

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Kira Dineen of DNA today. Thank you for listening