Cancer Prevention - Part 2

There are magical anticancer compounds in fruits and vegetables that can help in cancer prevention. Variety of colors matters in the diet. Let’s talk about some of these compounds. Indoles are found in white and green cruciferous vegetables. Things like broccoli, cauliflower and cabbage are the whites and greens. We know that cauliflower doesn’t have enough vitamin C, but it’s not the vitamins in fruits and vegetables that help in cancer prevention. Most of the vitamin studies have fallen short. It’s the colors, the pigments, that are the nutritional heroes that fight against cancer.

What do indoles do? They reduce the production of one of the stages of cell division in the cancer process. We also know that indoles can act as negative estrogen regulators and alter the effects of estrogen. Most of the breast cancer in women is estrogen receptor positive. What that means is that women are vulnerable to the increased amounts of estrogen. If indoles can actually down regulate that estrogen receptor, it may reduce the risk of the most common form of breast cancer. Research also suggests that they can be invaluable in the prevention of cervical and prostate cancer.

Are there creative ways that you can put more broccoli and cabbage into your diet? Think a little about it.

Lycopene is the red pigment. If the food is red it rules. Things like tomatoes, pink grapefruit and watermelon are great red foods. The whole fruit is preferred, but juices can serve as a reasonable substitute. Let’s say you’re travelling and you don’t have the availability of a fresh salad, but a can of tomato juice would be a great substitute. It’s not quite as good, but almost.

Multiple roles exist for lycopene in cancer prevention. It accesses an antioxidant, protecting those wonderful cell membranes you have. It may prevent abnormal cell division. Large epidemiological studies show a relationship between those who have low levels of lycopene in their blood and an increased prevalence of prostate cancer. However, currently studies haven’t demonstrated the prevention of prostate cancer through increased consumption of lycopene.

Cooked tomato products actually have an increased amount of bioavailable lycopene. When you are trying a veggie burger, put ketchup on it.

Spice up your food with some additional color. For the color gold, try turmeric. Turmeric, which is a traditional curry spice, is actually a cancer prevention powerhouse. A compound in it called cuncurmin is thought to induce the aberrant cells to die, rather than proliferate.

However, as we discovered with many dietary compounds, there can be some downsides to using turmeric. Turmeric, particularly when used as a supplement and not a spice, may reduce the effectiveness of chemotherapy. Sometimes compounds that are needed for cancer prevention actually are not a good idea during cancer treatment. This is where you need to talk to your physician. Sometimes good for prevention may not be so good during treatment.

What about yellow and orange foods like carrots and corn? In a recent study published in the American journal of clinical nutrition, carotenoids present in these foods were found to decrease the risk of breast cancer in post-menopausal women.

What about the other colors of the rainbow? What about some blue, purple and some additional red? Simply stated, think berries. Berries such as blueberries, raspberries and strawberries contain wonderful chemicals that can repair the DNA damage. Remember that the damage to DNA is the first step of cancer development. We’ll be reviewing more common dietary recommendations for cancer prevention in my next post.

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Cancer Prevention

Let’s talk about cancer prevention. What can we do to prevent it? Cancer is the second leading cause of death in the United States, and the most feared diagnosis. Although heart disease is the number one killer of Americans, the diagnosis of cancer is the most terrifying. Clearly we have much to do in the prevention of cancer. Poor diet is estimated to account for 30% to 35% of the cancers. Therefore, we can do something to modify our risk. Please keep in mind that modification of risk does not preclude the need for early detection and diagnosis. Although you might do everything possible in terms of diet and exercise, make sure you keep up with diagnostic testing.

Outside of diet, there are other lifestyle risk factors: tobacco use, alcohol consumption and lack of exercise. These can increase the overall risk of almost all cancers.

Here I want to talk about the dietary strategies and lifestyle modifications needed to reduce cancer risk.

Both tobacco and alcohol initiate and promote cancer development. Not only they cause cell damage, they also promote cancer development.

The American Cancer Society suggests that 1 million skin cancers could be prevented by eliminating sun exposure. This is a double edged sword. We know that the sun is a great source of vitamin D. By eliminating sun exposure, you can also eliminate one of your major sources of vitamin D. Sun screen can be very effective for preventing skin cancer, but it must be applied in an appropriate way. The higher the Sun Protection Factor (SPF), the better.

Exposure to UV light in tanning salons can be just as dangerous as exposure to the sun itself.

Some of the most exciting things in terms of cancer development is that we now know that certain viruses have been implicated in cervical cancer and possibly others as well. New vaccines can be given to prevent certain forms but not all of cervical cancer.

The current thinking is that nutrition can either act as a cancer promoter or a cancer-cell killer. According to the American Cancer society, diet and weight management can aid in the prevention of cancer. If you’re struggling with weight management and exercise, you might want to think about this as your deposit in the cancer prevention account.

There appears to be a dose-related response to exercise. That means that 30 minutes of exercise is good, but an hour would be better. Human bodies evolved to move. Apparently, in this case, what is happening is that individuals who do not exercise become resistant to insulin. They make of it, and the more you make, more you promote cancer development.

Simple Recommendations

What do you think of a plant-based diet? The more of your plate is occupied by vegetables, the better. Think about having a meat-less Monday, were your main dish might be vegetarian.

A recent study that included more than half a million subjects (this is a lot!!) suggest that those who consume the highest amount of red meat have a higher mortality rate. This study is known as the NIH-AARP Diet and Health Study. Mortality rates from both heart disease and cancer were increased with increasing red meat consumption.

What are some big recommendations from this study? Reduce the meat and avoid grilling. Grilling can increase the charring of that meat. It is the charred meat that can increase the risk of cancer.

Well, suppose you’re invited over somebody’s house and they are not really great with their grilling skills and you’ve got everything that’s significantly blackened. Trim off as much of that as you can and maybe flavor it up with a bit of barbecue sauce.

Regarding alcohol use in cancer prevention, the best approach is no alcohol. Keep in mind that alcohol minimally is going to serve as an initiating event. If you do drink alcohol, the recommendation is to limit your intake to one drink per day for women and two for men.

Avoid cured meats. These are processed meats, such as bacon, ham and hot dogs. Individuals are trying to get away from beef and pork, we now have cured turkey products. We have now turkey hot dogs and everyone believes that’s better for them. The problem is the curing of the meat. Cancer-causing compounds are formed when meats are cured.

Well, here I ended talking more about what we should avoid to prevent cancer. In my next post I’ll talk about a healthy diet and lifestyle that would help in cancer prevention.

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Genetic Engineering

Genetic Engineering is the manipulation of microbes, plants and animals to make products that are useful to people. As such, this technology is not new. It began a long time ago. I would say that biotechnology began with agriculture.

What is Genetic Engineering?

Estimates are that agriculture probably began about 10000 years ago, in what is now the region near Iraq. We have evidence that Sumerians living there at the time learned that barley plants growing around their homes made seeds that could be used to make bear and bread. They started growing these seeds near their settlements. They would use some of the seeds to make bear and bread, and then they would grow the rest of the seeds nearby. This was the first biotechnology.

A History of Genetic Engineering

Werner Arber was born in 1929. As a graduate student at the University of Geneva in the 1950’s, he studied with a physics professor who converted from doing pure physics to biophysics. Arber’s PhD thesis was on the phenomenon of bacteriophages restriction. He didn’t even suspect that his research would begin a revolution.

In 1973, scientists had taken two chromosomes, cut them open, put them back together, and showed that they were functional in a cell. They had created genetically functional recombinant DNA. It was a revolutionary discovery.

Review the timeline of genetic engineering.

Benefits of Genetic Engineering

The first major product of biotechnology was human insulin. This type of insulin is now used to treat type 1 diabetics. Another example is the blood-clotting protein that is missing in hemophilia.

There is a protein called Erythropoietin (EPO). EPO is a hormone-like substance made by the kidneys. The gene coding for EPO was isolated, EPO was made by recombinant DNA technology, and this is now widely used for people who are undergoing kidney dialysis and also people who are being treated with cancer chemotherapy.

There are a significant number of humans that lack adequate amounts of growth hormone. These people are very short in stature. The growth hormone is a protein. So, again, we got to get it through recombinant DNA technology.

We can use biotechnology to have a plant make a vaccine. You could become immune to a disease simply by eating a fruit. Pretty nice, eh?

These are just a few benefits of this new technology.

Genetic Engineering in Agriculture

According to UN estimates, human population will level off at about 10 billion people. Can biotechnology help solve this issue? A real problem in agriculture that existed for millennia is that most plants cannot grow in salty soils. Salt-tolerant transgenic plants may make deserts bloom again.

Other applications of biotechnology in agricultura are:

• Plants That Make Their Own Insecticide
  
• Plants Resistant to Herbicides
  
• Nutritionally Rich Crops

Problems with Genetic Engineering

The first supposed problem is that genetic manipulation is an unnatural manipulation of nature. This is what philosophers call the “yuck factor”. According to this argument, eating food from a plant that has genes from bacteria is just “going too far”. There is no real response to this emotional argument.

The second of the supposed problems is that genetically modified foods might be unsafe to eat. It turns out that most genetically modified plants grown today are not altered in the food part of the plant. We’ve got to be careful with allergies, however.

The third of the risks is that genetically modified plants may be dangerous to the environment. This is maybe a real risk, but not a really serious one.

The revolution that this new technology caused is profound.

Stem Cell Research

Stem cell research is in our news all the time, both from a scientific point of view and a political point of view. Today we’re on the threshold of stealing a power from the gods, the power to regenerate human organs and make life much longer. There are some people who fear retribution from the gods, but I know we’re going to do this anyway. Our scientists, no matter what the political climate is, are going to learn how to use stem cells to regenerate organs.

What are Stem Cells?

Stem cells are unspecialized cells in the body that constantly divide to form a pool of cells that can then specialize when they are needed. The ultimate stem cells are embryonic stem cells. They are totipotent. They can become any cell in the organism. In laboratory experiments on animals, these embryonic stem cells can be induced to form many different cell types. In animals, these cell types coming from embryonic stem cells have cured brain damage, heart damage, muscle damage, etc. This has generated great excitement for stem cell research.

The proposal is to use laboratory grown stem cells as a supply. You don’t need a lot of embryos to do this. The problem is that if I get some stem cells from someone else, they’re not mine. Those cells going into my heart would do the work, but then my immune system would ultimately reject them.

What is the advantage of stem cell research?

There is a need for new cells in medicine to replace cells that are damaged. For example, in a heart attack, the heart muscle is damaged, and it is usually permanent damage. How are you going to replace that tissue? In the brain, Parkinson’s disease and others result from a lack of functional cells. Diabetes, specially type 1, the pancreas is damaged. Let’s get new cells to replace these!

Stem cell transplants are already performed every day. Bone marrow gets damaged when cancer is treated with radiation therapy and chemotherapy. All the cells, including the stem cells inside the bone marrow, are damaged. A person who is treated with radiation and chemotherapy for cancer is going to be severely anemic and immune-compromised; because their immune system would not be working (white blood cells would not be produced in sufficient numbers).

Cancer

Cancer is one of the most intriguing and frustrating paradoxes of life. Life on Earth evolved because of the susceptibility to mutation that that’s inherent in DNA. DNA is a fragile molecule that is easily damaged. And these are the damages that cause cancer. If DNA wasn’t fragile, though, then evolution wouldn’t happen. This disease, however, seems almost like an inherent element of life as we know it. What causes it? What can we do to prevent is? Can we really cure it? Let’s find out.

Causes of Cancer

It can be attributable in about 80% of cases to external environmental causes. We must understand, however, the inner mechanisms of our bodies that go wrong for it to occur. One of the hallmarks of tumor cells is that they lose control over cell reproduction. I think most people know this, but there are other important defining characteristics of this disease.

There are some tumors caused by viruses. Tumor viruses were discovered in a very interesting way, in 1910 by Peyton Rous.

Inherited mutations in tumor suppressor genes can allow cells to divide inappropriately. It turns out that about 10% of tumors are inherited. This includes about 10% of breast and colon tumors. Compared to non-inherited ones (called also sporadic), inherited tumors typically occur earlier in life. For instance, inherited breast tumors would manifest in women during their 20’s, instead of in their 50’s, as it is common with sporadic cases.

Most cases turn out to be sporadic, so they need many mutations in order for the tumor to form. These mutations are caused by something from the outside. Common causes are carcinogens. They are divided into three groups: physical, chemical and biological agents.

Cancer Statistics

It is interesting to look at the statistics. Thanks to research we know many facts about its incidence and the factors that contribute to it. There is a very strong racial and geographical bias in who gets this disease and who doesn’t.

Cancer treatment

How do we treat and cure this fearsome disease? There are three ways to treat it: surgery, radiation and chemotherapy.

Breast cancer surgery has always been the first line of treatment for this disease, and remains so today, even though is the most invasive one. Surgery is the tool with which we can remove the bulk of the tumor most easily.

A second kind of treatment is radiation therapy. In this case we use high energy coming out of a radiation generator to create a release of energy within the patient’s DNA. Comparing this kind of treatment with surgery, radiation is going to give us excellent control of those microscopic margins, because we aim it in the area where the primary tumor is located, but also is going to have a wider spectrum.

In chemotherapy, we give drugs mostly intravenously. As you may know, within seven seconds they are going to get to virtually every cell in the body. The good thing about chemotherapy is that we don’t need a target. This is why it has become so important in metastatic tumors. We don’t need to know where the tumor cells are hiding, the drugs will get there. However, it is very toxic and it isn’t good for handling tumor bulk.

Chemotherapy

Here I want to talk about chemotherapy, its pros and cons. In this type of cancer treatment, we give drugs mostly intravenously. As you know, within seven seconds they are going to get to virtually every cell in the body. The good thing about chemotherapy is that we don’t need a target. This is why it has become so important in metastatic cancer. We don’t need to know where the cancer cells are hiding, the drugs will get there. However, it is very toxic and it isn’t good for handling tumor bulk.

There are a couple of things about this treatment that you need to know. There is something called the Goldie-Coldman hypothesis. This is a huge mathematical concept that I have no idea what is about. I know, however, what Doctors Goldie and Coldman found out. They found out that chemotherapy would fail even in very small numbers of cells unless you go the whole way and get all the possible metastatic cells. You cannot back off and get the same result.

If you’re getting a bad result with surgery or radiation you can always back off for the patient to rest and pick up again. In chemotherapy, however, if you don’t finish the course of treatment because of toxicity, then the patient is very likely to have a lot of resistant cells that escaped through natural selection. You’ll get the most resistant cells.

Goldie and Coldman also say that it’s very unlikely you’re going to be able to do the job with one drug. We usually don’t use one drug. We use multiple drugs so that we can lower the toxicity of each one. We try to get drugs with different toxicities. Maybe we use one that works maybe depressing the bone marrow, which is a bad thing. We may use another that has another toxicity and you get a synergistic effect that kills the cells you want to kill and not make the patient so sick.

Ideally we use eight or ten drugs, but we generally use two or three and try to get the patient to complete the whole cycle. Just about the time things are really getting bad for the patient we back off and pick up again later. These cycles are timed to try to get the cancer cells when they just caught their breath and started to multiply again. Meanwhile, normal cells have probably recovered pretty well.

It is very hard to measure the effectiveness of the treatment unless you have some tumor you can see. The most important type of chemotherapy is the category called adjuvant therapy. Adjuvant cancer therapy has a very specific definition. It means that it is given to a patient in whom we cannot prove that they have metastasis, but we highly suspect it.

What we found out is that if you wait until there are enough tumor cells to produce symptoms it is usually too late to get the best results from any treatment. If you move in to a patient who has microscopic metastasis, you’re going to get the best result. How do we know who that patient is?

Adjuvant therapy, therefore, is defined as drug therapy given to a patient without proven metastasis but who we think has a very high likelihood of having them. Doctors do all the studies they can and say to the patient: “Look, it is likely that you’re cured, but we’ve got a lot of bad biologic markers. We would do you a lot of good if we do the chemotherapy now, before this comes back three years down the road.”

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Radiation Therapy

A second kind of cancer treatment is radiation therapy. In this case we use high energy coming out of a radiation generator to create a release of energy within the patient’s DNA. Comparing this kind of treatment with surgery, radiation is going to give us excellent control of those microscopic margins, because we aim it in the area where the primary tumor is located, but also is going to have a wider spectrum. As opposed to surgery, radiation is not invasive and it has very few side effects and does kill cells. The problem is, though, you still need a target tumor, just as with surgery. We have to know where we are aiming it. You cannot radiate the whole body.

Also, you only get one lifetime anatomic dose. Once you have full therapeutic radiation, you can never have it again no matter how many years later. You’ve done enough damage to the blood vessels. If you radiate again on that area, probably you’ll cause death of any of the tissue you radiate.

Radiation doesn’t handle bulk very well. It needs a small amount of tumor cells, unlike surgery. It might be a good complement to surgery, however. Surgery handles the margins poorly, radiation handles them well.

The primary goal of radiation therapy is the injury to the cancer cells’ DNA. The wavelength used is such that radiation can cause a break in the DNA chain. The idea, however, is not to fry the cell. If you’re going to fry cells, you’re going to fry all the cells radiation goes through.

What we’re looking for with radiation therapy is to get the cancer cells to lose reproductive ability. We want the cell not to die because you boiled it up like an egg, but to make it so that when it tries to reproduce it just can’t. That may take several cell divisions before it falls apart, and that’s why radiation may take so long to show results. These cells have to go through a certain number of attempts to replicate before they finally die. Here we are making use of the fact that the fast-replicating cells are the cancer cells, so they are the ones dying. Most of our cells are resting, not replicating, so they are not going to feel the effect of radiation.

The dosages used are usually 5000 Rads or 50 Gray to a specific are, for example the whole breast. If you want to compare that with diagnostic radiation, a mammogram would be about 1 rad.

There are some cases of tumors induced by radiation therapy, but not nearly as many as other sources of radiation.

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Breast Cancer Surgery

Breast cancer surgery has always been the first line of treatment for this disease, and remains so today, even though is the most invasive one. Surgery is the tool with which we can remove the bulk of the tumor most easily. The good thing about surgery is that it removes the whole mass, whenever possible. A problem with it is that it requires a target. We have to know where the tumor is. This is often the case with breast cancer surgery.

Also, surgery is very invasive and we don’t get control of the microscopic margins. When we take out a cancer, it is very important that we leave no tumor cells behind at the edges. The way we do this is trying to go in and take normal tissue around the tumor as much as we can without causing destruction. In certain areas this is going to be easier than in others. For example, in breast cancer surgery we can usually take an area of normal breast tissue around the tumor, whereas in the brain everything you take will lead to destruction.

In breast cancer we have three operations we use to do. William Halsted, a very famous professor of surgery at John Hopkins, is considered the father of modern surgery. He invented rubber gloves for his girlfriend, who was a nurse allergic to disinfectants. He invented the radical mastectomy for breast cancer. With this, the entire breast was removed, and also all the pectoral muscles were removed, because he thought cancer spread through the pectoral muscles. We now know this isn’t often the case.

Around the 1960’s, doctors decided that that was too much surgery. We started removing the entire breast but leaving the pectoral muscles. After that, we moved into what is now called lumpectomy, where the tumor is removed with a little margin of normal tissue. Then, through a separate incision, we use to take out lymph nodes and do what is called a sentinel node biopsy. We inject either dye or radioactive material before the operation that will be picked up by the lymphatics and deposited in these lymph nodes. Then, we open up the axilla and we look for the dye. We take out the lymph nodes and we see if it contains metastasis. It is unusual for metastases to skip lymph nodes, so if it is clean, we consider that the tumor has not metastasized.

In order to see if this really works, surgical protocols were started about three decades ago. With many studies we found that lumpectomy with axillary dissection worked as well as the modified radical mastectomy, which worked also as well as Halsted’s radical mastectomy. Now, the lumpectomy with axillary dissection is the gold standard.

What we try to achieve surgery is to do less and less to patients in a surgical way, as it is so invasive. So far, however, we still have the need to do breast cancer surgery in a lot of cases.

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Good Things About Genetic Engineering

Here I want to talk about one of the good things about genetic engineering: using it to clean up the environment. I’ve already written about the benefits of genetic engineering in medicine and agriculture; let’s turn to the good things about genetic engineering regarding the environment. We can use bacteria as nature’s recyclers. Bacteria thrive on all sorts of nutrients, including things that we refer to as waste. There are species of bacteria that have the genetic capacity to produce enzymes that humans don’t. Composting uses bacteria to break down the carbon rich stores such as cellulose, which are the indigestible parts of wood chips, paper or straw. Also, they break down nitrogen rich sources, such as protein wastes and coffee grounds. When the bacteria work on these things, they produce four things: carbon dioxide, water, heat and humus.

Waste water treatment uses bacteria to act on human waste, paper products and household chemicals. The liquids and solids are treated differently. There is one group of bacteria that digest harmful substances in the solids of our wastes. Some of these bacteria, by the way, make a gas called methane as a byproduct, which is used for energy. Liquid wastes are digested by other bacteria. There is a whole series of bacteria that will digest different substances that are in things we call waste.

We’re still discovering more efficient and better ways to use bacteria for our purposes. This is called bioremediation.

Bacteria and plants have or can be given genes that remove pollutants. In addition to being nature’s recyclers, bacteria break down many human-made pollutants. How do we know this? We take soil with water, and we take that pollutant, oil for example. Then we look and see whether any of it gets broken down. We grow up the bacteria that thrive on the pollutant and use it.

In 1989, the oil tanker Exxon Valdez ran aground near the Alaskan shore, releasing 11 million gallons of crude oil over a thousand miles of shoreline. This was an environmental disaster of major proportions. Cleanup by physical methods was used first and the result was a dispersion of two thirds of the oil. Genetically engineered bacteria did the rest by bioremediation. Genetic strains of bacteria that can eat up oil were used. This process is ongoing.

The government of Kuwait is using bioremediation to try to clean up 150 million gallons of oil that was spilled probably deliberately by exploding oil wells during the Gulf War of 1991. This is probably the largest single remediation project in the world, and it is going on as I write. This is maybe one of the most useful of the good things about genetic engineering.

Good Things About Genetic Engineering? Environmental Cleanup

There is a type of bacteria called extremophiles. They have many genes that are useful in bioremediation. Extremophiles are bacteria that love the extremes of nature. They are kind of the ultimate athletes of the biological world. They can live in very hot places or icy places like Antarctica, or deep in the ocean, or very salty environments like the Dead Sea. These organisms form a separate group from bacteria called the archaea. They are called archaea because they resemble the organisms that are believed were the first living cells.

The archaea genomes have been sequenced and half of the genes of the archaea do not resemble anything in any types of bacteria or eukaryotes. Some of them have genes that use carbon dioxide, just like plants do, not to make sugars but to make methane gas. Archaea are by far the major producers of this gas.

The granddaddy of all archaea is called Deinococcus radiodurans. This organism lives in probably the most dangerous environment on Earth: ones with extremely high levels of radiation. Normally, radiation kills cells by damaging DNA. When DNA in any cell is damaged by radiation, we can repair it thanks to a system that we have. Large amounts of radiation, however, overwhelm that, and you get permanent mutations and cancers as a result.

Deinococcus radiodurans gets around this by having the most efficient and sensitive radiation repair system in nature. It is a phenomenally good system. This wonderful organism is responsible by one of the good things about genetic engineering. Genes from other extremophiles are being engineered into Deinococcus radiodurans. People call this new organism Conan the Bacterium. It is used to clean up the most toxic sites we know of. For example, in America there are sites extremely contaminated with extremely bad stuff. These Deinococcus radiodurans are being used there.

Plants can be genetically engineered for environmental cleanup. For instance, bacterial genes that allow environmental cleanup can be put into transgenic plants to break down oil. There are plants that would convert solid mercury into harmless substances. They might ask why use plants when microbes are available. The issue is that you want to get the microbe out of the soil when you don’t need it anymore. You don’t want extra microbes. Getting bacteria out of the soil is quite difficult. Plants are easy to take out. You plant it, it does its thing, and you take it out. This might be a better way of doing bioremediation in some cases.

Cancer Statistics

It is interesting to look at cancer statistics. Thanks to research we know many facts about cancer incidence and the factors that contribute to it. There is a very strong racial and geographical bias in who gets cancer and who doesn’t. The geography is interesting. In Japan, there was a very high risk of gastric cancers probably due to eating lots of smoke foods. That risk is starting to disappear as habits change. There was, according to many cancer statistics, a very low incidence of uterine cervical cancer in Israel probably due to specific sexual practices and circumcision.

If you look at some of the charts of cancer statistics in female population, there is an interesting change in trend in lung cancer. This has to do probably with the advent of the women’s liberation movement, which made it much more acceptable for women to smoke. Lung cancer rose at a dramatic rate.

It is interesting that the incidence of breast cancer stayed about the same, but the death rate from lung cancer now exceeds the death rate from breast cancer. There are more breast cancers still, but lung cancer is much more fatal. There is also a decline in colon cancer because of endoscopy. We started looking at colon cancers through the colonoscope and it turned out we can take out most of them in early stages. Now we are getting to these before they are full blown cancers and we’ve achieved a huge decline in both incidence and death rate.

Lung cancer is very high in Asia, where people smoke much more heavily than in this country. Primary hepatic cancer (cancer of the liver) is very high also in Asia because of a combination of something called aflatoxin. Aflatoxin is a toxin that comes from a fungus and they occur in poorly stored grains. Liver cancer is very common in Asia and Africa, and virtually unheard of in America. Maybe you’ve heard that someone got liver cancer, but I’m almost sure he doesn’t.

There is a difference between primary cancer and metastatic cancer. When a cancer starts, for example, in the breasts, that is called primary breast cancer. When that cancer spreads to the brain or the liver, it is still breast cancer. It’s not liver cancer. It is very rare to see primary liver cancer, meaning that the cancer started in the liver cells.

We see a lot of melanomas of the skin due to ozone depletion in the Southern hemisphere. There is big hole in the ozone layer right over Australia. Cancer statistics start to show a very high incidence of both melanomas and other kinds of skin cancers due to UV light.

There are racial factors in the incidence of cancer. Blacks, for example, are protected from the effects of UV light by the melanin, which are benign cells in the skin that filters out those lights. Skin cancers in blacks are much rarer.

Poverty is also linked to cancer. Just like it is with infectious diseases, it is not very good to be poor.

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Causes of Cancer

Here I want to talk about some known and common causes of cancer. Common causes of cancer are carcinogens, which are those things in our world that cause cancer. They are divided into three groups: physical, chemical and biological agents. In 1755, we probably had the first connection between cancer and an environmental agent. Percivall Pott, a pathologist in England, noticed that there was a prevalence of scrotal cancer in chimney sweeps. These were boys who worn an outfit, were tight to a rope and lowered down to a chimney, where they swept all the coal tar. These boys got these skin cancers on their scrotum. It was, according to Pott (and it turned out to be true), the constant contact of the coal tar against the scrotum skin. The interesting thing was that the French didn’t get this, because they washed their clothes every day. The English boys didn’t, so they had constant coal tar residues.

Four years later, John Hill noticed the association of cancers of the nose and the oral cavity in patients who chewed tobacco. He just made the connection; he didn’t know why that happened. Then, in 1950 there were two sets of investigators who ended a very long debate, noting the relationship between cigarette smoking and cancer.

This is the history of how we found environmental agents in the causes of cancer. There are three big groups of environmental carcinogens: chemical, physical and biological. Most carcinogens only produce cancer in a very small number of patients. Most of the time, our body’s defenses would prevent cancer from occurring. So, the connection between an environmental factor and a type of cancer is very difficult to establish. Most smokers never get cancer, for example, even though cigarette smoking is still one of our most common causes of death.

Tobacco is the most important of the causes of cancer. It causes 30% of cancer deaths (of all cancers combined). Everything else pales in comparison to this. If we got everybody to quit smoking, then we would have 2000 deaths a year from lung cancer instead of 200000 a year. The money spent on research and prevention could be spent in something else also.

Alcohol is also linked to cancer. When it is combined with tobacco, it is very potent in causing cancers of the mouth. How often do you see someone holding a drink who is also smoking?

Food additives are a small percentage of the causes of cancer. Food flavorings are one example. Certainly saccharine causes cancer in mice. The link in humans is still a little fuzzy.

Industrial chemicals: there are some industrial chemicals that are huge causes of cancer not only for the workers, but for people in the general population also.

Asbestos are microfibers that probably spear the cytoplasm and the nucleus of the cell. They probably also mix chemicals that never should had been mixed. They cause mesothelioma, a kind of cancer. There is an interesting controversy with asbestos. Asbestos in the ground doesn’t really hurt anybody. Miners have a problem, however. Asbestos in walls that are well sealed are less harmful than when you try to remove them, because that’s when you spread it to the workers. Leaving the asbestos where it is would probably do the most in preventing this kind of cancer.

Ionizing radiation: it is the kind of radiation which has a lot of energy and can move electrons in an atom. This could cause mutations in DNA molecules.

Electromagnetic fields: they are usually on the papers, but there is no hard evidence there had been cancer increases because of them. This is still very controversial.

Nuclear Energy: this is one that comes up a lot because of the fact that radiation is emitted. As far as we know, however, the industry of nuclear energy is pretty clean. There have not been increases in cancer deaths, except in places like Chernobyl. We did learn about cancer from Hiroshima and Nagasaki. We learned, unfortunately, how much radiation you need to get cancer.

Ultraviolet Radiation: we know that both types A and B of ultraviolet radiation are carcinogenic (skin cancer).

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Risks of Genetic Engineering

What are the risks of genetic engineering? The revolution that genetic engineering caused was profound. There was initially great concern about genetic engineering. The concerns centered on several aspects of this work. First, the bacteria used in these experiments were E. coli. This bacterium commonly lives on our intestines. People were worried about what will happen if this laboratory organism got out into our gut. Could the bacteria lead to cancer? This fear led almost to hysteria. Municipalities passed laws banning all genetic engineering work. A very famous scientist arrived to his laboratory one day to find the police out front, saying “you’ve broken our municipal ordinance against doing any gene swapping”. Doom scenarios were all over the place.

In 1975, a conference was held in California which brought together scientists, ethicists, physicians and lawyers to deal with this situation. This was a unique event in the history of science and government relations. The meeting was called by the scientists who were doing the work. They wanted some sort of feedback on what they were doing, because they were worried about the possible risks of genetic engineering.

At this meeting, after several days of heated discussions, they decided to do a moratorium on certain types of experiments. For example, until they knew what they were doing, they weren’t allowed to put cancer genes into bacteria to study them. They imposed extreme safety precautions on all of their types of experiments. Government agencies and institutional boards at research universities were set up to oversee this.

Scientists really asked for this oversight, which is very unusual, because scientists usually are of the type “just let us do our work and leave us alone, we would never harm you”. In this case, scientists were quite worried because this was so profound a change in biological manipulation.

In retrospect, these concerns were overblown, and no dangerous events have really occurred with genetic engineering. In fact, experiments that required severe precautions in 1975 are now done in high-school science labs. This doesn’t mean that we don’t need to constantly monitor this research. If we are dealing with harmful genes we must take extreme precautions.

Timeline of Genetic Engineering

This is a timeline of genetic engineering and genetics in general. It outlines the most significant events and discoveries that led to the genetic revolution.

2500 B.C.: Oral records describe the selective breeding of horses.

350 B.C.: Aristotle proposes that the genetic material is carried by the sperm, the female fluid organizes it.

A.D.:

1721: Boylston uses inoculation to prevent smallpox.

1766: Van Leeuwenhoek observes human sperm under the microscope and sees “tiny
Humans”.

1796: Edward Jenner provides evidence for the effectiveness of inoculation to prevent diseases.

1831: Charles Darwin begins his around-the-world expedition on the Beagle.

1858: Charles Darwin publishes On the Origin of Species. In it, he explains how natural selection of genetic variations leads to the evolution of new species.

1866: Gregor Mendel reports his experiments on pea plants, showing the patterns of genetic inheritance.

1868: Friedrich Miescher isolates DNA.

1895: Albrecht Kossel gives the initial descriptions of DNA’s chemical structure. He finds that DNA is a long chain of nucleotides: A, T, G and C.

1903: Chromosomes are identified in dividing cells as the probable carriers of genetic material.

1910: Peyton Rous discovers that a type of cancer in chickens is transmitted from one animal to another (he is awarded the Nobel Prize in 1966).

1928: Frederick Griffith’s experiment indicates a chemical structure of genes.

1934: Asbjorn Folling calls phenylketonuria a “genetic disease”.

1935: High-yielding wheat is developed in Japan by genetic selection and crosses.

1944: Oswald Avery shows that DNA causes genetic transformation in bacteria, pointing to DNA as the genetic material.

1950: Ernst Wynder finds a linkage between smoking and lung cancer in careful population studies.

1952: Alfred Hershey and Martha Chase demonstrate that DNA is the genetic material in cells.

1953: James Watson and Francis Crick propose the double-helix structure of DNA.

1956: Arthur Kornberg describes DNA polymerase, the enzyme that catalyzes DNA replication.

1958: A carrot is cloned from a single specialized (mature) cell.

1960: An unusual chromosome called the Philadelphia chromosome is found to be diagnostic in chronic myelogenous leukemia. Forty years later, a drug is developed specifically for the gene product from this chromosome.

1961: High-yielding adaptable wheat is developed by Norman Borlaug in Mexico. The use of this variety of wheat results in record crops in Mexico and India.

1962: A frog is cloned by nuclear transplantation from a specialized cell nucleus. Werner
Arber describes bacteriophage restriction and proposes specific restriction enzymes made by bacteria that cleave incoming phage DNA at specific sequences. Newborn screening for the genetic disease phenylketonuria begins. Its public health success results in other screening programs.

1964: Robert Holley determines the first sequence of a nucleic acid.

1970: Norman Borlaug is awarded the Nobel Peace Prize for breeding high-yielding varieties of wheat for use in the poor regions of the world.

1971: Daniel Nathans maps a viral genome using a restriction enzyme. The model for cancer involving tumor suppressor genes is proposed. This leads to the discovery of these genes and their control of cell division.

1973: Genes from different bacteria are spliced together in the lab and then put into a single cell. Soon, human genes are put into bacteria and expressed.

1977: DNA sequencing methods are developed and soon automated. This ultimately leads to genome sequencing projects.

1979: The human insulin gene is expressed in bacteria. This is first drug made using genetic engineering, and a new industry is born. Smallpox is eradicated through vaccination.

1982: A genetically modified bacterium is patented; upheld by the U.S. Supreme Court, this leads to many more patents of organisms and genes.

1984: The Human Genome Project is first proposed.

1985: DNA fingerprinting by repeated sequences is invented by Alec Jeffreys. It soon has many applications in forensics.

1989: Bacteria with genes for digesting oil are used in bioremediation of the oil spill from the tanker Exxon Valdez.

1990: The novel Jurassic Park brings DNA technology to public attention. A transgenic cow makes a human protein in its milk.

1995: The first genome of an organism is sequenced: a bacterium that causes meningitis.

1996: Dolly the sheep, the first cloned mammal, is born. Other mammals are soon cloned.

1998: Human embryonic stem cells are grown in the laboratory, making possible their use in medicine.

1999: Golden rice, rich in betacarotene, is made by genetic modification of rice plants. Debate continues on the possible dangers of genetically modified crops.

2000: Drafts of the entire human genome sequence are completed (the final sequence is announced in 2003).

2001: Salt-tolerant tomato plants are made by genetic modification, opening up the possibility of genetically adapting crops to the environment.

2002: Stem cells are isolated from fat.

2005: The chimp genome is completed, leading to comparisons with the human genome to find differences.

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History of Genetic Engineering

Let’s review the history of genetic engineering. A scientist named Werner Arber studied bacterial viruses. Bacterial viruses are also called bacteriophages, they eat bacteria. Arber was born in 1929. As a graduate student at the University of Geneva in the 1950’s, he studied with a physics professor who converted from doing pure physics to biophysics. This was the 1950’s, the DNA structure and the double helix had just been announced, and genes were the rage in science. Even physicists were catching the biology bug.

Arber’s PhD thesis was on the phenomenon of bacteriophages restriction. This is a phenomenon in which a specific type of bacterial virus can only infect a specific genetic strain of bacteria. The virus, with its body and DNA, lands on the outside of the bacterial cell, injects its DNA into the cell, and this DNA takes over the cell. Half an hour, that cell, which was converted into a virus factory, is dead.

Arber was specifically interested in the fact that only certain host cells seem to work for a particular virus. Other bacteria didn’t. Arber’s professor must have been really impressed with him, because their hire him in 1960 as a junior professor. In 1962, he and his graduate student Daisy Dussoix found that bacteria seemed to evade infection by viruses by chopping up the invading virus DNA into fragments. So, the virus DNA gets in, and all of the sudden gets chopped up in fragments.

Arber proposed the hypothesis to explain this phenomenon: virus restriction. First, host bacteria make an enzyme that recognizes a specific DNA sequence on viral DNA. Second, the bacteria have an enzyme that modifies its own DNA to make it resistant. This is what stops the restriction enzyme from chopping up the bacteria’s own DNA.

Arber’s hypothesis was soon confirmed in the 1960’s. In the US, at John Hopkins University, Hamilton Smith and his team isolated and described the chopping enzyme from bacteria. Because it only cuts DNA at certain sequences, they call it a restriction enzyme. The second point of Arber’s hypothesis was also confirmed. Arber himself characterized this system that modifies the bacterial DNA. Arber was doing only basic research, but his discovery was essential in the history of genetic engineering.

How is this discovery relevant in the history of genetic engineering? Scientists soon described other restriction enzymes that would cut DNA at other DNA sequence sites. Each of them was highly specific for a certain site. Earlier in the 20th century it was recognized that if you take a protein out of a cell, the protein would fold in the same it does inside the cell. The cell is mostly water, so if you take a protein and put it in water, it would fold the same way. This means that you can study and use proteins outside of the cell. This includes restriction enzymes.

First Success in the History of Genetic Engineering

Two scientists, Stanley Cohen at Stanford and Herbert Boyer at the University of
California San Francisco, saw the method of cutting DNA and mapping it in a test tube, and wanted to follow it up. Their idea was to take a DNA sequence, cut it, and put it back together again. At Stanford University, another scientist discovered that there is an enzyme that would put cut DNA’s together. Cohen and Boyer tried the experiment using chromosomes from E. coli (bacteria).

They had two different strains of bacteria. One bacterium had resistance to antibiotic A. Another bacterial strain had resistance to antibiotic B. They isolated chromosomes from both of these, put them in the test tube, and just how they planned, they cut the chromosomes open with the restriction enzymes, and glued the two chromosomes together. They took another bacterium that doesn’t have any resistance to antibiotics, and they put this new chromosome into it. Low and behold, this bacterium was now resistance in some cases to both A and B antibiotics.

It was 1973. These scientists had taken two chromosomes, cut them open, put them back together, and showed that they were functional in a cell. They had created genetically functional recombinant DNA. It was a revolutionary discovery. It meant that genes from any sources in nature could be taken out of the cell and swapped and spliced beside one another. We were no longer limited in genetics by normal processes like fertilization. This could be considered the real beginning of the history of genetic engineering.

Soon, within a couple of months, they had taken human genes in a test tube, spliced and put them into bacterial chromosomes. The bacteria did not turn into humans, it was a single gene that makes RNA. This could never happen in nature.
Arber and Smith both won Nobel prizes. The two California universities patented the method of making recombinant DNA and reaped millions of dollars in royalties. Boyer soon cofounded Genentech, the first genetic engineering company.

The revolution of genetic engineering had begun.

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Problems With Genetic Engineering

There is public concern about the possible problems with genetic engineering. At the start of the 1970’s, these concerns were more widespread, as we didn’t know really what we were doing. When this technology was shown to be safe, these concerns abated. The possible risks of genetic engineering, however, have been a public concern, especially in Europe. These objections are threefold.

The first problem is that genetic manipulation is an unnatural manipulation of nature. This is what philosophers call the “yuck factor”. According to this people, eating food from a plant that has genes from bacteria is just “going too far”. There is just too much technology here.

There is no real response to this emotional argument. Scientists would say: “Well, all major crops have been genetically manipulated by humans even before genetic engineering was invented, so, that’s okay.”

Well, genetic engineering is really different. We’re taking genes from all over the plant, animal and bacterial world, and splicing them together. We can’t offer a rational response to this argument. We just can hope that these concerns will abate, as has happened with in vitro fertilization, for example.

The second of the supposed problems with genetic engineering is that genetically modified foods might be unsafe to eat. Some modifications of proteins, for example, may create a structure in the protein that some people might be allergic to. It turns out that most genetically modified plants grown today are not altered in the food part of the plant. They have some extra DNA sequences, but they are not modified in the food part. We’ve got to be careful with allergies, however.

The third of the risks is that genetically modified plants may be dangerous to the environment. Although a single gene is being transferred to a crop plant (one that makes it resistant to insects, for example), that gene might be transferred also to neighboring plants. This has been observed in some instances, but not in others. There is a danger of creation of super weeds with resistance. This is maybe a real risk, but not a really serious one.

There are two ways to look at these public concerns. One way is to proceed with caution, to do as many tests as we can, and make sure something doesn’t cause harm. The other way to look at it is the precautionary principle. This principle says “if you can’t prove that this would never cause a problem, don’t do it”. This argument has been common in Europe, but less so in other parts of the world. Certainly, this argument isn’t made in the less developed parts of the world, where genetic engineering has become a major way of improving plants.

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Genetic Engineering in Agriculture, Part 2

Genetic engineering in agriculture overcomes some of the limitations of traditional agriculture. Until now, we’ve spent enormous efforts to adapt the environment to the plant. That’s what a farm is, an adapted environment with the purpose of maximizing the growth of a plant. Now, we have the possibility of being able to adapt the plant to fit the environment. Here I will list the limitations of traditional methods that genetic engineering in agriculture overcomes. Also, I’ll list some of the genetically modified plants in widespread use over the world today.

1. Limitation number one: in traditional agriculture they select specific traits (genes) for crosses, but at the same time other hidden genes that are not desirable may also be transferred. Using genetic engineering in agriculture, single genes are transferred.
   
2. Limitation number two: there are many genes in nature that can’t be crosses into crop plants because they are in different species. Using genetic engineering in agriculture, genes from any organism can be transferred.
   
   
3. Limitation number three: traditional agriculture is slow. Genetic engineering is rapid. You can see results in weeks.
   
   
4. Limitation number four: the ecological thrust of agriculture has remained to use genetics and technology to adapt the environment to the plant. With genetic engineering, the plant can be adapted to the environment.
   

Genetically modified plants are in widespread use. I’ll give you three examples.

Plants That Make Their Own Insecticide

Insecticides are chemicals that kill insect pests. The problem with insecticides, however, is that many of them are not specific. They target many insects, not just the pest. In addition, some insecticides are toxic to the environment in other ways. Insect larvae (the immature stage of insects) eat, among other things, bacteria.

There is a bacterium called Bacillus thuringiensis that has a gene that defends itself against insect larvae. This gene codes for a protein that binds to the insect larvae’s intestine, and makes it loose all of its fluids. The insect gets chronic diarrhea and dies.

The gene coding for this toxin protein has now been introduced to corn, cotton, soybeans and tomato cells. These cells were cloned to make plants that express the toxin in the leaf. As a result, the insect caterpillars land on the leaf, begin to eat and die very quickly. The population of this pest goes way down.

This technology has reduced insecticide use by 90%. This is an environment-friendly use of genetic engineering in agriculture.

Plants Resistant to Herbicides

Weeds can be killed by repeated applications of herbicides (chemical that kill weeds). These chemicals, however, very often kill beneficial plants as well, and even some crops. These are non-specific toxins. Great care is needed to use herbicides properly.

Genes had been identified from bacteria and other sources that code for proteins that break down herbicides. That’s how the bacteria survive to them. These genes had been isolated from the bacteria and put into cotton, corn, soybeans, rice, etc. As a result, these modified crops are now resistant to the herbicide. The herbicide can be applied without any risk of damaging the crop. These crops are in widespread use all over the world.

Nutritionally Rich Rice

Rice grains are deficient in their protein, in terms of their amino-acid balance. There is an ongoing effort to improve that. In addition, rice does not make a substance called beta-carotene. People require beta-carotene, which gets converted into vitamin A, in their diet. Rice plants do not have the gene to make beta-carotene. As a result, about 250000 children go partially blind each year. They are eating rice, and they don’t get enough beta-carotene in their diet.

Other organisms have the genes coding for enzymes that can produce beta-carotene through a biochemical pathway. Ingo Potrykus isolated DNA for each one of these enzymes. One of them was from a bacterium, the other genes happened to be from a daffodil plant. One by one, over a period of a decade, he took each one of these genes and introduced them into a rice plant, along with a promoter that would stimulate gene expression in the developing rice grain.

The result is a rice plant that made grains with beta-carotene. These plants are now being crossed with local varieties all over the world to make the beta-carotene phenotype part of rice that is used in different regions of the world.

Genetic Engineering in Agriculture

Let’s talk about genetic engineering in agriculture. As we know, genetic engineering allows transferring genes from one organism to another. How is this useful in agriculture? We’re faced with a challenge over the next 50 years: feeding an ever expanding human population. According to UN estimates, human population will level off at about 10 billion people. Can genetic engineering in agriculture help?

A real problem in agriculture that existed for millennia is that most plants cannot grow in salty soils. When soil is irrigated, that is when people bring water to dry soils, the water also brings salts. This temporarily allows plants to grow, and normally these small amounts of salts get removed from the soil by rainfall. In dry climates, however, there isn’t much rain. As time goes on, salt builds up.

Salt build up has always been a major problem in agriculture. It led to the fall of civilizations. For example, the Mesopotamians fell as a civilization largely because of salt build up in their soil. Today, it is estimated that up to 65 thousand acres of farmland a day are lost to excess salt build up. The soils are essentially rendered unusable.

Salt is toxic to plants in two ways. First, salt impairs the roots from taking up water. Second, salt blocks several of the enzymes involved in important processes. How does it do that? It alters the way that these proteins fold, and if an enzyme folds incorrectly it won’t be able to do its function. The particular enzymes I’m talking about are involved in making proteins, and also some involved in photosynthesis. Photosynthesis is the process by which a plant converts solar energy into stored energy in the form of sugars.

Few plants in the world can thrive in very salty soils. Certainly, not the major crops (rice, wheat and corn). Finding a gene for salt tolerance in these crop plants is unlikely. If you go to the crop seed bank, it’s likely that you’re going to find a variety of rice that has a mutation that makes it tolerant to salt.

Scientists always use “model organisms” to do research. The model plant is a tiny mustard like plant, called Arabidopsis. Arabidopsis is a model for the genomes of the major crops. Arabidopsis does all the things that the major crops do. It has roots, stems, leaves, flowers and all those things. It is useful to study it because we can grow it in a greenhouse near a laboratory and we know its entire genome.

In the 1990’s, Eduardo Blumwald found that Arabidopsis has a gene that is expresses as a protein which suck ups salt form the soil, and put it into storage depots inside of cells called vacuoles. These particular cells are in the leaves of the plant. This might be a pretty good way to tolerate salt. The salt would never get into the rest of the cell.

The problem comes when the salt build up in the soil is very high, as happens in soils that had been rendered unsuitable for agriculture. There isn’t enough of this protein, so the excess salt leaks out of the vacuoles and gets into the rest of the cells.

Using genetic engineering, Blumwald has added a vector with a very active promoter (a section of DNA that turns on a gene) beside the gene that allows the salt to be stored in vacuoles. So, the expression of this gene would be enhanced. When he made transgenic plants using this vector, the genetically modified Arabidopsis was able not just to withstand salty soil, but to thrive in it. What an amazing thing!

Blumwald didn’t really want to grow Arabidopsis on salty soils, but to get this gene into crop plants. Genetic engineering allows transferring genes from one organism to another. When the active salt-tolerance gene from Arabidopsis was put into a tomato plant, it became very salt-tolerant. A normal tomato plant would wither and die in a salty soil, whereas the modified tomato plants would be just fine. What’s more, the salt was in the leaves, the tomato fruits were just fine.

While tomatoes are important, they are not nearly as important as the major grain crops. So, Blumwald and others are busily trying to transfer this salt-tolerance gene from Arabidopsis to rice, wheat and corn.

This may make salty soils in the world usable for farming. Salt-tolerant transgenic plants may make deserts bloom again.

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Ten Facts About the Human Genome

1. Of the 3.2 billion base pairs in the human genome, less than 2% code for proteins. 98% of the genome is not coding for proteins. There are 24000 genes in a human. Rice, for example, has 35000 genes. What is going on? I think I’m more complex than a rice plant.
   
   
2. 99% of the human genome is identical in all people.
   
   
3. The functions of many of the 24000 genes in the human genome are not yet known.
   
   
4. Genome sequencing is getting faster and cheaper. In 2007, the genomes of James Watson and Craig Venter were made public. It took those genomes two months each to get sequenced, with a cost of about 1 million dollars each. The price is going down and down. The objective is to reach the 1000$ genome by the next decade.
   
   
5. Genome sequencing of individuals is useful for: screening for possible diseases, genetic research and origins research.
   
   
6. We have fewer genes than a rice plant. There are three possible explanations for this, but the basic one is that we can do many things with each gene.
   
   
7. Genes are interrupted in their information sequence by non-coding sequences, called introns. Introns are kind of nonsense. Every gene has so many introns that the coding regions can be mixed and matched together. Each human gene gets translated into about 5 proteins.
   
   
8. After a protein is made, it folds into its three-dimensional shape, but other things can happen to it. Sugars can be put on to proteins and change their functions. We can have a set of genes that add sugars to various proteins. These modifications add to the diversity of proteins that can be made.
   
   
9. There is a big chunk of the human genome that makes RNA’s that don’t get out of the nucleus, that don’t end up getting translated into protein. These are very small RNA’s called micro RNA’s (mRNA). They were very recently discovered. In fact, they aren’t even in most textbooks. In the human genome, these small RNA’s may be involved in gene regulation (turning a gene on or off). We’re not quite sure what these mRNA’s are doing, but humans have a lot of them.
   
   
10. Scientists used to say that 98% of the human genome that doesn’t code for protein is junk. It looks like this junk has a valuable function. The junk does have some gems there, the mRNA’s.

The Genome Project History

What is the genome project history? Well, let’s review history. In the closing days of World War II, the United States exploded atomic bombs on the Japanese cities of Hiroshima and Nagasaki. Hundreds of thousands were killed. Many more were exposed to radiation. These survivors, and their descendants, had been intensively studied ever since that time for increases in mutations and their effects on people (especially cancers). By the late 1970’s, methods had been developed to get the sequence of DNA molecules. With this technology, scientists were able to study mutations and genetic diseases in much more detail. In 1984, Nobel laureate Renato Dulbecco made the daring suggestion that we should sequence the entire human genome. If we did that, we could compare the people who were not exposed to radiation to those who were, and we could get a very good handle on genetic damage. It’s not surprising that the first sponsor of what came to be known as the human genome project was the US department of energy, which oversaw the radiation damage project.

The human genome sequence was determined in two ways. There was a huge challenge: chromosomes are extremely long (on the average 100 million base pairs of DNA). Machines could sequence 800 base pairs at a time. So, we cut the 100 million base pairs into 800 bases fragments. How many fragments are those? Well, that’s your assignment. Hint: it’s a lot.

When we determine the sequence of each of those fragments, we just stick them together. Oh, yeah? How are we going to fit them together? How do you know which fragment is which? It’s like taking the Bible, cutting each word and putting them on the floor. How do you line them up?

There were two methods to get some kind of signposts by which we could say “this belongs here”. The methods were called hierarchical sequencing, and shotgun sequencing. Hierarchical sequencing was done by the government sponsored Human Genome Project. This was sponsored by many governments from around the world. Thousands of scientists worked on this effort, and it was led by Francis Collins.

They tried to recognize short sequences of DNA that were at certain landmarks all the way down the chromosome. If that short sequence is on the left end of the chromosome, for example, and then you randomly sequence fragments and you see that short sequence you’ll that belongs on the left end.

It took ten years for scientists to look at all the human chromosomes and get these landmark sequences. Then, they arranged them. It took about 15 years to do this human genome sequencing.

The other way to do it is called shotgun sequencing. Shotgun sequencing was done by private industry, led by Craig Venter. They did the same thing using with landmarks, but they had a computer to find them. This took amazingly sophisticated computer analysis. A whole new field was developed for this shotgun sequencing effort: bioinformatics. This was much more rapid, it took only a year to sequence the human genome.

The complete human genome was finally published in 2003.

Cancer Treatment

We’ve seen what cancer is and what we think causes it. What about cancer treatment? How do we treat and cure this fearsome disease? There are three ways to treat cancer: surgery, radiation and chemotherapy. Surgery is by far the most common cancer treatment. Removal of a tumor that is localized can cure cancer. Much of cancer surgery in recent years has become conservative of the surrounding tissue.

Radiation is used in cancer treatment on localized regions that can’t be removed in surgery. This might be in a very diffuse area, for example. It also might be useful to shrink a tumor that is up against a vital organ and the surgeon is afraid of damaging that organ. Radiation damages DNA, it causes both strands of DNA to be broken. The amounts of radiation used are small from the military viewpoint, but quite large from the medical one. Let’s illustrate this. The lifetime exposure to radiation of a typical person on Earth is about 0.12 gray (a physical unit). During the course of radiation treatment, the tumor itself gets 50 gray over five weeks. That’s 400 times the lifetime dose.

The third method of cancer treatment is called chemotherapy. It is used when tumors have spread over the body, because when you put a drug in the blood system, it will be distributed everywhere. Typical chemotherapy uses drugs that kill all dividing cells, including the tumor. There are side effects to chemotherapy. Normal tissues get affected, like bone marrow, cells in the intestines and skin.

A wide array of drugs that block cell division have been isolated and are used. Some are natural products we get from plants, others we build in the laboratory.

A Real Life Case

This is a real case involving cancer treatment with chemotherapy. John first noted that he tired easily at the gym. It got worst over several weeks. When he began to have shortness of breath even when he walked from room to room, he decided to see his physician. When his doctor looked at a drop of blood under the microscope, he saw many white blood cells. A blood sample was sent to laboratory, and they confirmed that he had over 200000 white blood cells per milliliter. This is 40 times normal. An hematologist looked at bone marrow as well as the blood and found a lot of immature white blood cells. In addition, he saw an abnormality: a funny looking chromosome called the “Philadelphia chromosome”. The diagnosis: chronic myelogenous leukemia.

No one knows how, but in this disease, the DNA in two chromosomes inside an immature white blood cell is cut and spliced. Two chromosomes exchange material, so that part of two genes that are ordinarily on separate chromosomes come to be right beside one another. The shuffled chromosome that was seen in John’s white blood cells was first noticed by scientists in Philadelphia in 1960, that’s where it got its name. White blood cells carrying this strange chromosome are stimulated to divide very rapidly. This is why they found this huge number of cells in John.

John was first treated with standard chemotherapy. He was given drugs designed to kill any reproducing cell. One of the drugs bound to DNA. A second one blocked the assembly of amino-acids. A third drug blocked the mechanism that partitions chromosomes to new cells. These drugs have bad side effects on other dividing cells. Using this conventional cancer treatment, John’s white blood cell count went down from 200000 per milliliter to 80000 per milliliter. This is still 16 times normal, however.

The drugs that John took blocked cell division all over the body. They were non-specific. John’s oncologist now tried a new approach: a specific drug. In the 1990’s, the molecular biology of this type of leukemia was described in detail. The new gene found in the Philadelphia chromosome was sequenced, and its protein product was studied. The protein turned out to be a terrific cell-division stimulant. It causes cells to divide without control.

Next, chemists at a drug company went into the laboratory and designed a brand new substance: a chemical that would specifically bind to and inactivate this new gene product in the tumor cells. At the University of Oregon, Dr. Brian Druker coordinated a clinical trial in which patients with chronic myelogenous leukemia were given this drug; to test for its safety and then its effectiveness. Patients like John, whose blood concentration of white blood cells was still high, were given the new drug and the result was spectacular. In John’s case, his white blood cell count went down to a normal 5400 per milliliter. He was cured.

The development of this drug, which is called Gleevec, is a great example of a new molecular approach to cancer treatment. The aim is to find out precisely what’s going wrong in a tumor cell and design rational treatments on this basis.

Precise molecular descriptions of the chemical biology of cancer are leading to new drug treatment for cancer and targeted chemotherapies.

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What Causes Cancer, Part II

This is a continuation on the last article on what causes cancer. In my last post we’ve seen how cancer is a multi-step disease, caused by a sequence of genetic changes, or mutations in certain genes. Here I want to look at the inherited or external factors that cause these mutations, and are thus what causes cancer. There are a couple of ways we can get these genes mutated or changed. One of them is to bring an active oncogene (a gene that helps a cell turn into a tumor cell) into a cell. If a cell has an oncogene that is not being expressed, a virus can actually bring it into the cell.

Cancer Caused By Viruses

Tumor viruses were discovered in a very interesting way, in 1910 by Peyton Rous. He got a call from chicken farmers in Long Island. The chickens were all getting these horrible tumors. So, he thought it might be an infectious disease. He went to Long Island and he showed that there was a virus that was spreading form chicken to chicken and causing these tumors (sarcoma). He isolated the virus and then infected an animal that didn’t have the tumor. The animal got the tumor, and from the tumor in that animal, he isolated the virus and repeated.

Rous was awarded the Nobel Prize in 1966, 56 years later. Why did it take that long to recognize him? Because no one really wanted to believe that cancer could be a communicable disease. People started to look at proteins and DNA, and attention shifted.

Tumor viruses, as it turns out, have actively expressed oncogenes. There is a tumor virus that has an actively expressed oncogene for that growth factor. When these active oncogenes get unto our cells, they stimulate cell division. Approximately 10% of human cancer is caused by viruses. In our society there are two major ones that are important: hepatitis B virus is associated with liver cancer, and a papillomavirus (warts), which causes cervical cancer. In both cases the good news is that antiviral vaccines are being used and developed.

Inherited Cancers

Inherited mutations in tumor suppressor genes can allow cells to divide inappropriately. It turns out that about 10% of cancers are inherited. This includes about 10% of breast and colon cancer.

Compared to non-inherited cancers (called also sporadic), inherited tumors typically occur earlier in life. For instance, inherited breast cancer would manifest in women during their 20’s, instead of in their 50’s, as it is common with sporadic cancers. These inherited tumors also appear in numerous places.

After looking at the data, Arthur Knudson proposed the “two-hit” hypothesis. From Mendelian genetics we know that most cells have two copies of every gene. Knudson proposed that for tumor-suppressor genes both copies have to be mutated. Both alleles of the tumor-suppressor gene must be off. People with inherited cancer have already in all of their cells one bad allele. So, if they later get a mutation of the second allele, they’ll get a tumor. That can happen reasonably soon. People who inherited two normal alleles, however, need two mutations, and that’s going to happen somewhat later.

Cancers Caused by External Factors

Most cancers turn out to be sporadic, so they need many mutations in order for the tumor to form. What do I mean by many mutations? Mutations must happen not only on the tumor-suppressor genes, but also on oncogenes and metastasis genes. You need all these events to occur in a sequence.

A doctor at John Hopkins University, Bert Vogelstein, and his colleagues, spent a lot of time during the 1990’s looking at the sequence of genetic changes that lead to cancer, specifically to colorectal cancer. This cancer develops first as a small group of cells. This group gets larger and larger over time. You can actually follow this. In colonoscopy, the objective is to remove the group of cells before it becomes a tumor. If you remove the cells, you have a sample of an early cancer.

What Vogelstein did was to make a survey of all the genes involved in cancer in these groups of cells as they went through the stages of development. What he found was a very dramatic series of events. First there were mutations in tumor-suppressor genes, and then there were mutations on oncogenes. Then there were mutations in metastasis genes.

Describing cancer in this amount of molecular detail is an amazing achievement of modern biology and medicine. It would lead to treatments.

So, when we are talking about something causing cancer, we mean that they cause these genetic changes. DNA can change in two ways. First, there are spontaneous mutations that occur during DNA replication. This means that people can get cancer without getting exposed to any bad stuff. This is rare event, but think of the fact that the body has trillions of cells, and cancer can come from one cell that goes bad.

The second type of mutations is induced ones. They are caused by something from the outside. Most cancer mutations are caused by the environment. Cigarette smoke, for example. The chemical compounds present in cigarette smoke damage specific tumor suppressor genes. Ultraviolet light from the sun causes skin cancer.

However, these things are obvious. For the case of most cancers, we really don’t know what’s going on. In fact, many carcinogens are natural substances in the diet. In most cases, we just haven’t identified them yet. They’re not the things you might think of. They’re natural molecules that plants make to defend themselves. How do we know this? Because there are country differences in cancer incidence. Also, when someone moves from one country to another, they and their offspring will adopt the cancer rate of their new country. When you look very carefully at it, you find that it’s probably diet.

This is probably why cancer is so difficult to treat or prevent: in most cases we don’t even know what causes it.

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What Causes Cancer

What causes cancer? We all know that cancer cells are different from normal cells. One of the hallmarks of cancer cells is that they lose control over cell reproduction. Normally, cells control when and where they reproduce. They do it in two ways. There are internal controls. Normally, there is an internal clock inside a cell that triggers in the cell division cycle.

Most mature(specialized) cells do not divide. Immature cells divide rapidly (think of an embryo or bone marrow). What keeps cells dividing is a group of proteins that stimulate them. What keeps them from dividing is a set of proteins that blocks them from cell division. Because they block tumors from forming, we call them tumor suppressors. These proteins act the control points during cell division.

Cancer cells have defective tumor suppressors. They have mutations in their DNA that causes the protein that normally functions to block cell division to not function. Those are the internal controls of cell division.

There are also external controls in cell division. The external controls are hormone-like substances called growth factors. They stimulate cells to divide by acting like a gas pedal in a car. For example, a blood clot forms and then the wound heals, so the skin around the blood clot heals, and the clot goes away. The cells that surround the blood clot have to be stimulated to do so. Those cells have to surround the blood clot and close the wound. “Closing the wound” is not a biological term, what really happens is a lot of cell division. In turns out that the same cells that form the clot stimulate the cells above it to heal. The clot makes a growth factor that stimulates the skin cells to divide, reproduce and heal the wound.

Genes whose protein products stimulate cell division in this way are called oncogene. Cancer cells usually make their own growth factor. They would have an oncogene that is mutated, so it is producing constant stimulation for cell division. Other cancer cells may have genetic changes that make them hypersensitive to even tiny amounts of growth factors. These are the genes that turn on the gas pedal of cell reproduction.

The most fearsome aspect of cancer is that cancer cells can spread to other organs. This is called metastasis. You can’t do surgery if a tumor is all over the place. This leads to multiple organ failures, and it is really what often causes people to die of cancer.

Normal cells have a “glue” that causes the cells to stick to one another. This glue is specific. If you pinch your skin, you will notice that the cells at the skin stick together and are separate from the bone. They must have a specific “glue”, which is formed by proteins. There are cell recognition and adhesion proteins. Cancer cells loose this adhesion.

There are several steps in metastasis. First, cancer cells have to loose their adhesion and detach from the tumor. Then, the cells make it to the bloodstream or lymph system. In the blood, they travel to an organ. They stop at the new organ and grow as a satellite tumor. We know all of these steps in great detail at this point.

This events: inactivation of tumor suppressors, activation of oncogenes and metastasis; occur in sequence. Cancer is a multi-step disease. To be continued…

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Benefits of Genetic Engineering

What are the benefits of genetic engineering? The benefits of genetic engineering are the products we can make with it. Genetic engineering could be used to make products in two ways: we could take the existing organisms and modify them genetically to make them more efficient. We could for example add a promoter that would make the organism produce more of one kind of protein. The second use of genetic engineering is that we can take new genes and insert them into organisms that never had them before.

The first major product of genetic engineering was human insulin. Insulin is a protein that acts as a hormone to stimulate uptake of blood sugar into tissues, such as the liver and the muscles. In diabetes, people don’t make insulin. Previously, insulin came from slaughtered animals. The insulin protein has 51 amino-acids. The insulin from slaughtered animals is similar to human insulin, but very often is one or two amino-acids different. It still has the same function, but the human immune system will recognize these one or two differences. So, in a significant number of diabetics, when taking non-human insulin, their immune system reacts against it.

Here, what we need is human insulin. Insulin is made in very small amounts. So, the only way to get this in reasonable amounts is by amplifying the expression of genes for insulin in recombinant DNA.

At City of Hope Medical Center in California, Keiichi Itakura went into the chemistry lab and made the insulin gene. It wasn’t even then a big deal to make it. Itakura’s colleague, Art Riggs, took this gene and put it into an expression vector, right next to a promoter. The expression vector now had the gene and a marker. The expression vector was then put into bacteria, and the bacteria expressed human insulin. This is about 7 or 8 years after the first emergence of recombinant DNA technology.

The insulin then was extracted, sent to a drug company, and then to physicians. This is the source of all insulin now used to treat type 1 diabetics. This is really the great example of a genetically engineered medication.

Another example is the blood-clotting protein that is missing in hemophilia. This blood-clotting protein can be supplied with genetic engineering. People no longer die of hemophilia thanks to genetic engineering. So, here we have two clear benefits of genetic engineering.

Proteins used to treat diseases

There is a protein called Erythropoietin (EPO). EPO is a hormone-like substance made by the kidneys. It enters the bloodstream, goes to the bone marrow and stimulates the production of red blood cells. Red blood cells only last about 120 days, so they must be constantly replaced. There are many people with kidney failure for various reasons. These people are treated with kidney dialysis, because kidney transplants are limited.

The kidney filters out the poisons and keeps the good things. In this case, all you can do is to filter the bad things with the dialysis machine. Among the things that get filtered out is EPO. So, these people with kidney failure have kidney function restored by dialysis, but they’re not making EPO. They have severe anemia. The only way to get around this is by massive transfusion or to treat them with EPO.

The gene coding for EPO was isolated, EPO was made by recombinant DNA technology, and this is now widely used for people who are undergoing kidney dialysis and also people who are being treated with cancer chemotherapy. Many of the drugs used in chemotherapy destroy bone marrow cells.

EPO is also the first genetically engineered drug of abuse. Athletes found that if they take some EPO they can increase their blood cell count. Increasing the amount of red blood cells by about 10% can give an athlete an edge in competition. There had been great controversies in cycling and elsewhere because of the abuse of EPO.

In Animals

Plants and animals can be genetically engineered to make products useful for us. The great example of this is diary animals. Sheep, goats and cows produce a lot of milk. Biologists found that the expression of genes for the major milk proteins is under the control of a promoter. This promoter is a sequence of DNA that causes the adjacent genes to be expressed in the mammary gland. It is called the lactoglobulin promoter.

This sets up a really nice opportunity for using genetic engineering. You could take the gene you want expressed in milk and put it into a DNA vector. Then you put this vector into a sheep egg cell. If you do this, the egg can then be developed in the laboratory for a couple of days until it becomes an embryo. You can insert the embryo into a mother and the offspring that are born are sheep that would make milk which contains this extra protein. This was actually behind the reason for cloning Dolly the sheep.

There are a significant number of humans that lack adequate amounts of growth hormone. These people are very short in stature. The growth hormone is a protein. So, we can get that protein from the body, but it is made in the pituitary gland in extremely small amounts. So, again, we got to get it through genetic engineering. The gene was isolated, put into a vector, put into cows, and there is a herd in Argentina of ten cows that in their milk will supply the world need for human growth hormone every year. This process is called pharming, and a very promising technology.

In Plants

Plants can be genetically engineered to make useful products. Genetically engineering a plant is a lot easier than animals. We don’t need to inject and expression vector into the fertilized egg of a plant, because plant cells are totipotent. We can take any plant cell grown in a laboratory, put the vector in, and then grow the plant up from that cell.

Plants produce a lot of protein. For example, tobacco plants have been genetically modified to make TPA in their leaves. Tobacco leaves are very large and it is easy to get the TPA from them.

You’ve probably heard the term antibody. Antibodies are what the immune system makes to fight diseases. A “plantibody” is a plant is making a human antibody. We can use genetic engineering to have a plant make a vaccine. For example, the vaccine against bacterial meningitis has been expressed in the fruit of plant, a banana plant. The people still have to eat the fruit, but it doesn’t have to be refrigerated and you don’t need health professionals to administer it.

We can create plants with new capabilities. For example, a major component of detergents is lauric acid. This molecule is made in a biochemical pathway in tropical plants, such as coconuts and palm trees. A major source of it is palm kernel oil. Scientists pinpointed one of the key enzymes that is in the biochemical pathway for making lauric acid. Scientists pinpointed the gene in palm trees, they cloned the gene into an expression vector and put it vector into rapeseed plant that produces canola. Normal canola produces oil that is 0% lauric acid. This particular transgenic canola makes 60% lauric acid.

There is a viral disease caused by the tobacco mosaic virus. This is a major pest of tobacco. It doesn’t kill the plant, it kinds of destroys leaf tissues and spreads very rapidly. This virus reproduces in the cells but doesn’t kill the entire plant. The viral genome can be replaced with other genes; in this case, with genes for vaccines. Now, instead of making a lot of proteins in viral particles, these tobacco plants are making large amounts of a vaccine. This may be a new use for what is widely grown crop around the world.

These are just a few benefits of genetic engineering. I’m sure more are coming in the future, as we discover more and more about genes and proteins.

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