Ask Beth: “Do you think there are instances where people do not process chemicals properly and therefore need support from supplements to aid in the processing of them?”

Sometimes I get asked good questions from friends with inquiring minds. I thought I would share them in case anyone is asking these same questions.

To answer this question, I will break it up into 2 parts:

1. “Are there instances where people do not process chemicals properly?”

Yes, there certainly are, and unfortunately, this results in a lot of disease conditions. For example, people may be born with a genetic mutation where a gene that makes one of the hundreds of enzymes in mitochondria that does not function properly. The enzyme may be responsible for a chemical reaction to make something or break something down. They are what “process chemicals”.  If you lack the enzyme that makes something, then you will lack that product. If you lack an enzyme key in breaking things down, the byproducts of that specific metabolic pathway will build up and can be toxic. There are an array of mitochondrial diseases. These are disease, and if you are missing an enzyme because of a genetic mutation, you would have serious symptoms, and in some cases if not treated, will cause death. Many of these mitochondrial diseases can cause bleeding in the brain and present as child abuse (without a positive skeletal survey revealing broken long bones or ribs common in infants who have brain bleeding due to child abuse), which is another interest of mine.

Here’s one example:

  • Propionyl coenzyme A carboxylase deficiency

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Figure 1. A very beautiful 3D schematic of Propionyl coenzyme A carboxylase. The alpha and beta subunits move and interact together to “do chemistry”.

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Figure 2. The work propionyl coenzyme A does in your mitochondria all day long without you taking a vitamin supplement.

  • Inheritance Autosomal recessive.This is a ‘mitochondrial’ disease since the deficient enzyme – propionyl coenzyme A carboxylase – is located within the mitochondria. Encoding genes have been found on both chromosome 3 (beta subunits) and 13 (alpha subunits).
  • Metabolic features: The neonatal form presents with increased ammonia levels, erroneously suggesting a urea cycle defect. Ketosis, acidosis (metabolic and lactic) and hypoglycemia are found in conjunction with increased glycine levels (see above in methylmalonic acidemia). For the aforementioned reasons the disease is also called ‘ketotic hyperglycinemia’. The co-factor of the enzyme is biotin; hence other enzyme deficiencies (multiple carboxylase deficiency, see later in 3-methylcrotonyl coenzyme A carboxylase deficiency) related to impairment of the biotin cycle (holocarboxylase synthetase, biotinidase) may cause diagnostic problems.
  • Clinical features: The disease has a severe neonatal (80–90%) and a milder infantile (10–20%) onset variant. Skin rashes, hypotonia, lethargy, dehydration, seizures and irregular breathing are seen in the neonate before severe acidosis leads to coma and death.
  • Clinical course: Prognosis in the late-onset form is much better. If the ketoacidotic metabolic crises which are often triggered by infection, fasting, constipation or high protein intake are successfully prevented, affected patients may reach adult age.
  • Treatment: Low protein diet with l-carnitine supplementation. (copied from http://www.mrineonatalbrain.com/ch04-17.php)

2. “… and therefore need support from supplements to aid in the processing of them?”

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Figure 3. A bobcat.

Enzymes are a type of protein and function as the work horses in our body. Let’s use an analogy that bobcat is one type of enzyme/protein- it has a 3D shape, it moves in space, does work, “processes chemicals”, vitamins are like the oil that keeps the bobcat running, and ATP is the gasoline. Vitamins lower the energy required for the enzyme to work – less gasoline/ATP. How do we get our enzymes? Sometimes  “food mysticism” literature (internet), implies that we are passive to our food and that we can digest key enzymes in raw milk or raw food. However, our GI tract does not absorb proteins/enzymes. The pH of the stomach is around 4 and then peptidases in the small intestine rip enzymes/proteins apart. Our intestine actually absorbs amino acids- sometimes as long as 3 amino acids in a row, but not proteins. Going back to our bobcat analogy, if we eat a bobcat, which is a protein in a steak, it will get homogenized in our stomach and then in our small intestine peptidases chop up the bobcat into parts- the fender, the tire, the wheel, the smokestack and then specific transporters for each part move it across the gut epithelia into our body. The inside of our small intestine is actually “outside” of our body, which is good as it has billions of bacteria (another interesting topic). Your gut epithelia is like the Berlin Wall- only very specific things can pass through. Also, vitamins pass through via their specific transporters and each type of nutrient gets across very specific transporters. What does your body do with these bobcat parts? The bobcat parts get absorbed into your blood and diffuse across capillaries when in your tissue, let’s say your bicep has a low concentration of arginine (an amino acid) as it’s constantly turning over muscle. Arginine, a bobcat part- let’s say a tire, would be transported into the muscle cell and if your muscle cell is deciding to make bobcats that day, it’s DNA, which is transcribed and then translated would instruct the cell to add arginine (a tire) to a bobcat it’s making or maybe another protein, let’s say it’s making myosin that day… a corvette. It would pop that tire on from the bobcat it ripped apart in your small intestine and then put it on a corvette in the cell in your bicep.

Our bodies are incomprehensibly complex and are robust factories that make very specific products on it’s own very specific agenda due to orders and communications from within the cell, the cell’s neighbors, hormones from the gut, hormones from the brain etc.. It is not passive. We eat food, our body rips it apart, and then decides what it wants to make with the parts. Of course, if you have a genetic mutation in an enzyme, including enzymes that process vitamins, you are going to have problems.

If you were unable to make a bobcat… or a corvette.. or any other key protein, you would have a disease. There is a very large area of scientific inquiry to try to solve the problem of how to correct mutated genes to make proteins we need. Sometimes it’s as simple as giving more of the protein that is missing (or being destroyed by your body)- like giving insulin in diabetes. Mitochondrial disease or any other metabolic disease, there is a huge effort to learn how to genetically engineer cells to give them the correct DNA to make the right protein (or bobcat) themselves. I have a friend who is a PhD student at MIT working in one of these labs doing very crazy theoretical things with DNA so that these disease where a protein (the parts of our cells that process chemicals) that is defective is corrected at the level of the DNA.

A big part of “food mysticism” is that vitamins are given more power than they have. You could give as much vitamins as you want to a person with a mitochondrial disease, but a.) if you one of your proteins isn’t working you have a disease, b.) if your DNA makes bobcats without pistons- no amount of oil is going to help. People with mitochondrial disease can manage their diet to decrease the activation of pathway involving the defective enzyme, but you can pour oil on your broken bobcat all day and it will not work. “Food mysticism” usually mixes in things that are correct: yes, it is possible that some people may not process chemicals properly, and yes, we do need vitamins +  incorrect information to get you to buy something (or click on a website which generates add revenue), but incorrect processing would lead to disease which would need a lot more treatment then the vitamins they are trying to sell you.

In conclusion, if you have a protein that’s not doing it’s job correctly, you have a disease that would need to be treated with medicine or altering your diet to avoid that metabolic pathway so you don’t die. Vitamins don’t help these conditions.

Note: Vitamin D is really the only vitamin that is found to be deficient in people not living in third world country based on scientific evidence— especially people living in regions with long winters. Though vitamin deficiency is obviously a problem, it does not mean that adding more vitamins is helpful if you are not deficient and vitamin supplements are actually associated with increased incidence of cancer and other problems.

Grant submitted!!! with 75 minutes to spare…

This past week as been a bit of an adventure heading towards the approaching deadline. The NIH has hard deadlines. If I missed this one, I couldn’t reapply until October or so and all the dates on everything would have to change. The bulk of my part was done about a week ago and then I had to various phase of hurry-up-and-wait as people go through it… and Nehemiah is out of school so he is tagging along for the hurry-up-and-wait. He’s been very patient as long as we get out of the house for hiking or visiting a park at least once a day.  There are two components- the 12 pages of science and then the 75 other pages of letters, biosketches, and other administrative pages- and routing it through 10 people at MGH and Partners. I submitted the rough draft 10 business days before then a few days ago Partners research management came back with 30 little things that needed to be changed in the 75 other pages and my boss did her final edits on the science end.

Besides the 11 letters in the grant, which I had to get creative in photoshop to make them fit the page limitation, I needed 3 external letters that the referees submit themselves into NIH. I requested 4, 1 declined a few days before the deadline. My two PhD references had their letters in earlier this week and the one MD submitted his last night at midnight. I have come to realize that MD’s and PhD’s have very different definitions of “last minute”. ha ha.

I submitted it to final route 24 hrs before it was due and then at noon today the woman at Partners tells me the NIH rejected it because it was on the wrong form and that form has expired. AAAAAAAAAHHHHHHHHHHHHHHHH… fortunately, I did not vomit. I found the updated form (99% the same exact thing) and started copying the old form to the new form, but my computer kept crashing with them both versions open- the PDF is a form where upload other PDF’s and my computer doesn’t like one open nevermind two open. AAAAAAAAHHHHHHHHH So I had to print it out.. but I have no printer at home… so Nehemiah and I raced to the church to print it out (usually I go to Staples for non-church issues, but time was an issue here). Fortunately, our departments admin person had me covered and filled out the new form and re-uploaded all my stuff into it much quicker than I could.

Then…. the person at Partners submitted it but there was an error. They told me to go into my NIH account, but my password wasn’t working…finally after 15 min of fixing my password I got in and realized I didn’t need to actually get in the account myself. Then I thought they were saying I needed to re-submit the corrected grant myself so I was trying to figure that out for another 15 min…. but turns out I didn’t have to. Anyways.. .despite ALL OF THAT.. it was submitted with a whole 75 minutes to spare…

Looks like I will have plenty of new fodder for future anxiety dreams…

Love your bacteria

I thought this was an interesting piece on the role of good bacteria on our skin and how washing kills a type of bacteria that is very good for skin.

http://www.nytimes.com/2014/05/25/magazine/my-no-soap-no-shampoo-bacteria-rich-hygiene-experiment.html?_r=0

Bacteria used to be a bad word, but I think people are beginning to realize that 99% of bacteria are good and if you get rid of the good ones, the bad ones can proliferate. Of course, there’s the data that kids growing up on a farm or with a pet have a lower rate of allergies. Dirt is good; however, when it comes to personal hygiene it’s interesting to dig into all the cultural dogmas wrapped into it. I only bath my kid about once a week/ when he smells and never felt compelled to do it more frequently than that as it usually takes kids a while to start smelling. I’ve never done the hand sanitizer or antibacterial soap thing- mainly because I know that soap alone kills bacteria so it’s marketing gimmick. Now I’m thinking, maybe I should lay off the soap. The other reason is my theory that our immune systems were created for a reason- to kill stuff, and if you don’t have enough for your immune system to do it gets bored and starts in on bad patters like autoimmune disease and allergies etc.

I’m hoping the next word that have a cultural shift is “chemicals”. “Chemicals” seems to have been equated with all things bad and “unnatural” these days. I think the world (and internet) would be a different place if more people took several semesters of college and graduate level chemistry courses, but alas, a whole industry would be put out of business. We are made of chemicals and chock full of hormones. Even little baby boys are pumping out their own steroids that actually make their brain develop into the masculine type brain. Give me an organic beet and I could isolate the chemical that gives it the red color and the structure looks very similar to a red color made in a lab. Your body is its own little lab churning out chemicals and hormones 24 hrs a day. Acid is acid whether it comes from vinegar or from a different bottle -it’s chemical that likes to donate protons. Of course there are certainly bad chemicals-  ones that trick your own hormone receptors into activating or toxins. DES, agent orange, pesticides, stuff that leaches out of plastic… all bad ideas. I’m personally very impressed with my liver as I was injected with known toxins- chemotherapeutic agents on several occasions, yes, it was awful, but my liver took care of it and my body healed itself. One of my chemotherapy agents could have even been derived “organically” as it comes from the bark of a type of tree in Oregon. Fortunately, they synthesize it in the lab these days so “no trees were harmed” for my cancer treatment. If detoxifying required conscience actions on our part we would all be dead already. Take a moment and thank your liver and your kidneys for detoxifying all day long, 24 hrs a day without even having to follow a recipe on Pinterest!

Writing Zombie

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Writing as a profession sounds so romantic. Visions of a cabin in the woods or on the ocean in the Florida Keys with a fisherman sweater, beard, and pipe come to mind… but alas…. that is not so for me. I write science. Last weekend, exhausted on a beautiful Saturday afternoon in May, I was in my son’s twin bed writing and eating out of a jar of peanut butter. I write at work. I write on the train. I write in bed at 4:30 am. I write in bed when my son goes to bed. I write on my couch… and apparently, I write in a toddler bed. When I drive my car, I think about what I am going to write. For the past 5 months, I’ve been working on four grants. The last for this round is due in 3 weeks, then I will take some vacation, and return so I can write… manuscripts.. I have 3 now piled up that need to be published.

Very few people actually know what I do. What I do can change from year to year and month to month. In 2012-13 we had a huge grant where I spent 6 hrs of the day on my feet or running down a hall. It was physically grueling, but great for recovering from breast cancer treatment because I didn’t need to think a whole lot. It was kind of like shift work with some thinking to problem solve the mitochondrial respiratory assay that wasn’t working… Now with all the sitting I do, I look for opportunities to walk or stand. I’m not sure how much longer my back can take it. I’m trying not to covet the walking desk a PI has down the hall from me.

When I tell people I’m writing grants some think it’s like writing a grant to get a piece of playground equipment… or some undergraduates say they write grants in college (sure….). I always wonder what that means when an undergraduate or recent graduate claims they did grant writing for a lab they were in….. did they write some of the administrative pages…. find some papers for the person who actually was writing the grant (the PI)… get the PI coffee???

So here are some scientific writing factoids:

1. You have to have data to write anything. Unlike writing fiction, no one wants to hear from you unless you did an experiment and have data.

2. This means you have to, a.) design good experiments (requires synthesis and knowledge of vast bodies of literature), and b.) get things to work in the lab (problem solve), have skills, and work and/or get other people to work (management skills), and c.) CREATE! Yes, being a scientist is creative, but very few people understand what you created. Rare is the patient who knows the scientist that created the treatment that cured their cancer etc. It’s like top secret art that very few people will ever appreciate… the opposite of performance art.

3. Everything has very specific space limitations. Therefore, even though I would like to wax eloquently on the subdural space and if there is actually a space and summarize an interesting literature review I did on the anatomy 5 years ago- it won’t fit. Being a scientific writer means that you read every other type of literature and edit in your mind all the words and details you would remove. I am about to finish Oliver Sacks’ “The Mind’s Eye” and I can tell you that he has not written scientifically. Yes, he is a very interesting neurologist who writes large volumes about science, but has not published scientific papers. If he had written scientifically, his books would be 75% shorter.

4. The current average age for a PhD at the time they get their first RO1 is age 45. An RO1 is the standard large grant from the NIH for a single scientist somewhere in the ballpark of $5 million over 5 years. Once you have an RO1, you are considered an independent scientist. Therefore, let’s say you get your PhD at age 27- it’s another 15-20 years of training! It used to be one postdoctoral fellowship (3-4 years). Then it was standard to have 2 postdocs… and in this current funding environment a PI may have a handful of scientists in their lab working towards their first RO1. As a result, there are an ever increasing amount of “training grants” to get you from the postdoc to your first RO1. This is what I’m working on now. To get an RO1, you need dozens of publications and have generated good, interesting data that will impact human health.

5. The grant body of my current grant has 12 pages limit.

6. I have spent about 250 hrs on those 12 pages- so far. it’s dense.

7. The entire grant application will be about 100 pages total including 12 letters of support and administrative pages. Learning how to do all the administrative pages and budget work etc. is quite the undertaking if you’re in a small lab who does not have a person who specializes in that. Fortunately, I have had lots of experience doing the administrative pages for other’s people’s grants and a few for my own applications.

8. The NIH instructions for the grant given by the NIH including all the instructions for the administrative pages is 200 pages long. If you are proposing experiments that involve people (clinical trials), there is a 100 page supplement of instructions. I have a writer’s workshop manual on how to specifically organize each section that is 170 pages long. About 30 pages of this manual is instructions on how to write the specific aims page that is 1 page. It has instructions for every sentence on that 1 page.

9. The average reviewer will spend 15 minutes reading your grant.

10. I don’t have stats for the success rates of grants, but you have to be the persistent type and not be afraid by the possibility of failure nor discouraged by failure.

11. As my boss says, “the difference between those that accomplish things and those that don’t is those that accomplish things do it.” My PhD advisor liked to “brute force” approach to science- experiments… publishing papers… grants.  After this round of grant writing, I may come up empty handed, but in the process have honed my skills of grant writing.

12. You learn by doing.