Jeff Bonadio's first lecture:
this module has one overarching goal and that is to help you understand the term genotype to phenotype correlations. To do that I will use one example that thread through the lectures throughout the next couple of weeks in which there is an altered genotype's and as a result of that there is an altered phenotype.
In other words there is an inherited mutation and it causes a disease.
At every step along the way we're going to try to make comparisons and contrasts between what is going on inside the cell. What is going on biologically, medically and what is the outcome of all this. One way of thinking about a genotype and phenotype. If you end up at the end of this module understanding the relationship between phenotypes and genotype's and some of the various manifestations of this relationship, then that would be great.
The way that we're going to do this is with four lectures and two labs.
Jeff goes over the syllabus
Jeff wants to go over what a disease is this lecture
flow is from gene to biochemistry to extracellular pathology
a bio engineer approached the problem of
(Jeff is going very fast using many complex new terms and the students do not answer his questions)
Jeff will spend a little bit of time talking about what it's like in medicine working with genotype phenotype correlations
working in vitro cells in culture
working in vivo using animal models such as mice
working in silico modeling of biological systems using a computer
biology in the 21st century is rapidly becoming and information science
This is the main point of where we sit today and looking over the next century
The terms of genotype-phenotype correlations what is the impact of sequencing genomes on our ability to deal with issues in human medicine?
The concept of scanning the human genome of wants in an economically feasible way is rapidly becoming possible using microchip technology
Was the sequence of your genome and what does it say about human health?
Such a scan in essence might predict all the diseases of person might suffer throughout the course of their life. It is an implicit forecast of life span and likely cause of death. The statements have come from the New York Times.
the way we do things now ( as opposed to possibly five years from now) is to work from phenotype to genotype. We asked which gene is mutated and use that information to help us understand the disease. With gene array technology the whole process is flipped. Start with the genome and predict what's going to happen. This is a revolutionary approach to medicine and biology and has implications for what it means to be normal and what means to be diseased.
The concept of personalize therapy is related to the ability to do genotype-phenotype type correlations was genomics as the underlying technology.
At the time of birth a sample of umbilical cord blood will be taken, DNA will be prepared from the blood, the genome will be sequenced, and into the database, and on the basis of this it can be screened or queried and predictions about the kinds of things in your life it should be avoided can be made.
Through an decision support system a physician might prescribe a series of recommendations or lifestyle changes to prevent or avoid potential disease or other health problems.
The idea will be examined in some detail today. I hope by the day you will gain a better understanding of whether this is possible or not, whether this is a serious possibility in your lifetime or if it's very far off in the horizon.
The homework for you today is for you to comment on whether you think this is something that you will see in your lifetime. The
It's more than just disease. It could be whether you're an extrovert or an introvert.
is your personality truly in your genes? Behavior, intelligence, sexual orientation; what does it mean to be normal?
We can scan your genome sequence said annotated and make predictions about what your life may hold for you as a result of the complement of genes in your genome.
Jeff reads at length from a quote from The N.Y. Times.
If we can fix everything, then what is a natural life span?
do you want to live to be 150 or not? You don't want to live to be 150 because it's bad for the planet?
Jeff makes statements about if people knew there going to live for ever then no one would be motivated to achieve anything early in their life and the productivity of our society would decline tremendously. No one says anything. Jeff says " come on come on you can't be neutral about all this "
you've got to think about this, it's important. Otherwise I wouldn't waste my time and your time talking about it, right? Jeff talks about one of his favorite books:
Why do we develop disease at all? Any ideas? ( no response)
something to think about is: what is normal and what is abnormal?
If you can't address the question of what is a disease that it will be very difficult to think about geneotype phenotype correlations
Jeff talks about the evolution of human history and the types of causes of morbidity and mortality throughout human history
early on it was trauma
early human society evolves against the Environmental conditions around the
early societies where relatively disperse and therefore there was no way for diseases to be amplified.
Populations may be restrained: Jeff makes a claim that it was common practice to eliminate a substantial portion of normal children perhaps up to 50%
Culling and was a practice that is used to titrate depopulation size against the ability to support people based on Environmental conditions.
It also appears to be common to eliminate children who were handicapped.
So was it like in terms of disease patterns? We know that the main causes of death were accidents, food shortages, predation from animals and parasitic diseases.
Generally speaking to people are undernourished making their immune systems susceptible to disease particularly parasitic diseases.
Diseases such as Alzheimer's, osteoarthritis, osteoporosis, cardiovascular disease did not exist because people did not live long enough for these diseases develop.
an important point to remember is that our genome is essentially the same as the genome of the people that lived 100,000 years ago. and under a dozen years is not enough time for significant changes to accumulate in human gene pools.
We're doing today with these diseases is trying to adapt to a radically different environment. About 10,000 years ago or so there is a switch between nomadic lifestyles to agricultural lifestyles.
There's a greater amount of food per unit of land. This causes population growth and pressure, tools for this were well known before it was put into place, people think although it's not been proven, that as the population expanded became easier to produce more food which then further promoted population growth. 6000 years ago was the beginning of domestication of plants and animals. Now population is much more dense and population growth is more rapid. Death rates are high; now they're not buying because of accidents but because an infectious disease. Almost all human infections are zoonoses; meaning that animals are vectors that did not get sick.
right now we're in a period of industry or post industry. Our genome hasn't changed, but environmental conditions have changed profoundly.
We're beginning to live much longer and obviously die at older ages.
Pretty soon expect that almost 50 percent of females are going to live past hundred.
Diet has changed, lifestyle change, and people are dying from non communicable diseases.
There is also a relationship between public health and the use of antibiotics. In the 1830's, the rates of tuberculosis were very high.
with this in mind how is this person approached problem of classifying diseases?
There are two types of diseases. Prenatal and postnatal. Postnatal diseases and require interactions between the genome and the environment. Prenatal diseases is a disease that is determined at the time of fertilization. It operates as a disease process regardless of the environment. The concept is that our genome is fixed and were not so well adapted to the changes in our environment. Prenatal diseases are of two kinds: chromosomal defects and single gene disorders. There are some others but for the purposes of our discussion these are the two that are most important. A significant number of these and up as stillbirths, they're not live births. an example of this is Down's syndrome.
We can talk about these diseases as being unifactorial. Osteogenesis Imperfecta is an example of this. Diseases of poverty and diseases of affluence. Diseases of affluence are new diseases arising in human history as a result of the Industrial Revolution. Such diseases may be smoking for example. If the rate of lung cancer increased following the rates of smoking. The ticks about 20 years to integrate the disease and there's a direct ecological relationship between the amount of smoke that gets into your lungs and the chance to you will have lung cancer.
maladaptive diseases is an idea that everyone wants to leave you with at the end of day. Wear and tear diseases - joint breakdown in old age for example.
The kind of thing that people are talking about predicting on this scenario is your susceptibility to diabetes. The question is do you think that by screening cord blood you be able to make a prediction like this?
What kind of prediction is this?
It would be empirical. It would be based on associations. Right? Would it be quantifiable? How many variables to think there would be in the genome database? Do you know how many transcripts there are? 150,000. How much time is involved? Is there any way to quantitate the number of transcripts and the time, and the regulatory loops involved in normal physiology and homeostasis? These are the things that have to think about.
Another thing that we haven't talked about is that cigarette smoke damages the carbohydrates in the lung lining and this will not show up in a genetic screen.
One of the things that gets damaged overtime in postnatal diseases is the genome. therefore there is no way to make accurate predictions about postal diseases using a cord blood DNA screen. now this is completely not true when it comes to prenatal diseases. They have very strong markers that would be present in cord blood DNA screening. The biggest problem is the ability to predict multiple interactions between weak markers.
Jeff asks if they think it's important to have this life signs of an engineering? Some may have a thought about why biosciences are important?
The estimate is that in 20% of U.S. businesses will be Life Sciences based in your lifetime. We're trying to expose you to this because society needs a new generation of Engineers that can work on problems that are biology related. Manufacturing recombinant proteins at scale for example would be something a smart chemical engineer could do.
Manufacturing genes at scale for gene therapy is another problem. We can have all the technology in the world want but we still need engineers to help us to manufacture things at scale. these engineers need the training so that they can talk to life scientists. bioengineering for example has produced joint implants to help people live much longer. Engineering has had a tremendous impact on our society and engineering in the Life Sciences is the next frontier. Interface between computer science and engineering and biosciences and genome sequencing is a very exciting new field.
Most engineers with traditional training have no idea up of how complex things are in the natural world.
Jeff has talked about in theoretical terms some things about it prenatal and postnatal diseases, and the interaction of the genome with the environment and how important this is for postnatal diseases but doesn't matter all for prenatal diseases
talked about disease patterns and how they've changed over the past 100,000 years and that they have nothing to do with changes in the genome
now talk about two examples of disease to make it as real as possible: first a prenatal disease, then a postnatal disease.
Survival curves for women in the United States.
this is changing radically over the course of the 20th and 21st century. Living longer is one of the things that contributes to changing disease patterns.
Survival curves for atherosclerotic cardiovascular disease.
1900's-not much of this disease at all.
Over a hundred years there is an increasing trend in death rates from at atherosclerotic cardiovascular disease. this is why cardiovascular stents are such a big deal.
Survival rates for heart disease have turnaround largely in the past 30 years as a result of bioengineering. death rates have come down as a result of advances such as pacemakers and defibrillators, anticlotting drugs etc., but it will still be the number-one killer worldwide for some time to come.
The genome didn't change at the Environmental conditions did.