Biology in Space

In this blog post, I want to talk a bit about the highly interesting human long-term space habitation experiments and its influence on the genome and epigenome. The final data are not out yet but we got some pre-results we can be excited about.

We live in an exciting era, the new space age.  Humankind starts thinking and planning to establish a stable human settlement on Mars and the Moon like in science fiction movies. Since Elon Musk takes care of the transportation problem of this vision, let us think about the other existing problem of this adventure. Humans and of course all other living organisms evolved on earth. That means since the beginning of life on earth one constant on earth was the 1g gravity. Organisms evolved from the beginning with gravity. Gravity is an important part of the development of animals and plants.

To figure out how organisms would react in space, scientists established a new field of research – space biology. Space biology investigates what kind of impact of space related environmental changes like weightlessness and radiation has on organisms. For this purpose, NASA and other space agencies perform a lot of experiments since decades but the most exciting one to answer one of the key questions started on March 27th, 2015 when Scott Kelly started his yearlong space mission at the ISS. This was a novelty; no human being was before one year in space without any interruptions. Additionally, this experiment has a huge advantage which excited all geneticists. This study was an identical twin study. While Scott Kelly was in space his twin brother Mark Kelly stayed on earth. That means that all differences in his body could be traced back on his space habitation. During his space habitation, samples were taken from Scott and Mark to investigate the difference in his physiology parameters and their genomes. The question “What influence has a long-term space habitation on the human genome” could be investigated. And for me as an Epigeneticist to answer this question is highly thrilling and would elucidate the possibility of future space missions to Mars and permanent settlements on other celestial bodies.

The mission ended on February 29th, 2016 and scientists started the research and analyzed the data. It has not been published a scientific publication yet. Very likely related to the enormous amount of data which has to be processed, but on Nature.com was a news article published, informing about some of the new findings. In the article, scientists speak about the following preliminary results without going into much detail.

1.      Different gene expression levels

2.      A change of the telomere length

3.      A change in the overall genome methylation level.

I would like to elucidate the preliminary data a bit but would like to concentrate on the last finding.

As Dr. Mason (lab) points out that a change in a gene expression, which simply means that genes have a different activity, is normal due the change of the environment. Our gene activity is plastic and not static. So during the change of habitation in a microgravity environment, it is expected that Scott Kelly’s gene activity is different but in his case, the activity change of genes is larger than normal. Since we do not know yet what genes have a higher or lower activity it is hard to get more information out of these findings. We need to wait until the results are published and then I will break it down.

The second finding is that the telomeres, the end of the chromosomes became longer during the space habitation. This is very surprising and the opposite was expected as Dr. Bailey describes the finding. Telomeres are connected with the process of aging and become shorter after each cell division. In the results, older humans have shorter telomeres than younger people. After Scott Kelly returned to earth his telomere length returned relatively quickly to his pre-flight length. To figure out what that means NASA started an additional study which will be completed in 2018.

The third finding is that DNA methylation is decreased during spaceflight, said Dr. Feinberg. DNA methylations are a chemical marker within DNA which can affect gene expression but the impact here is much higher than that. First I want to explain what DNA methylation exactly is and why a general decrease of it could lead to a problem for human settlements.

DNA methylations are simply the addition of a methyl group (-CH3) to 5’-carbon of the cytosine base in the dinucleotide 5’-CpG-3’ in CpG islands in the promoter region of genes (1-3).

Simplified: The region which determined the activity of a gene contains very often an enrichment of the bases cytosine and guanine (the other ones are thymine and adenine) in the specific order cytosine ( C ) – guanine ( G ) or CpG (the p describes the phosphate bond between the two bases). These enriched regions called CpG islands. A methylation of the C in many of the CpGs prevents the gene to be active, it is called epigenetically silenced. This process is reversible and not permanent. So when Scott Kelly’s overall genome experienced a decrease of methylation it is assumed that genes, in general, become more active. This would also explain the first finding of a very different gene activity. What does it mean when many genes become active which were inactive or silenced before? Imagine the genetic program, especially the epigenetic program as a song played on a piano. Each key is a gene and when you push it down you hear the sound and the gene is active for that moment. In order to play a song on a piano, you have to push and release the keys in a certain combination, order, and length. This illustrates how complicated the genetic program is. Now imagine further that all keys are pushed at the same time in our example it would mean that they are all active, they experience a lack of control, a lack of methylation. This analogy is very simplified and exaggerated but it illustrates the problem a lack of overall methylation will cause.

Further, DNA methylations and its regulation are essential for the development (4, 5). So regulate DNA methylations the X chromosome inactivation, the genomic imprinting and control the transcription of retroviruses and transposons (6).

X chromosome inactivation: Female humans have 2 X chromosomes but only one can be active in each body cell. That means there is a need in silencing a complete chromosome in each cell. This process is controlled by methylations and calls X chromosome inactivation.

Genomic imprinting: Male and female humans have a different pattern of active genes just because of their gender. Some genes are active in females and are inactive in males and vice versa. This is important for the right development and a deregulation could lead to disorders like the Prader-Willi and/or Angelman syndrome.

Viruses and transposons: While the evolution humans picked up a lot of viruses and transposons. These integrated themselves into the DNA and over time were permanently silenced to prevent damage to the genome. Especially, transposons or jumping genes are able to change positions within the DNA and causes point mutations when they leave and could cause gene inactivation where they re-enter. Therefore they became permanently epigenetically silenced. A decrease in an overall methylation would cause an activation of these viruses and transposons.

Conclusion: For me as an Epigeneticist a decrease of the methylation has a big impact. As I pointed out what happens when the methylation pattern loses its control, the question remains what is the reason for this loss of methylation and can it be prevented from happening. Also the fact that Scott Kelly’s epigenetic pattern recovered shows that a one year in space has not a permanent impact onto the epigenome.

Scott Kelly lived one year in microgravity and since the human body is not used to this environment, the body reacts which stress. This stress causes the changes described above. Back in gravity, the body is able to recover. If the reason for this methylation decrease during the space flight is caused by microgravity the question occurs how much gravity is needed to maintain the normal level of methylation to guarantee the health of the astronaut and for the offspring of hypothetical future space settlers.

To establish a permanent settlement on any celestial body, the genome of humans needs to remain intact. That means to prevent mutations caused by radiation which causes cancer and to maintain a normal gene regulation which includes the methylation pattern. On Mars, we have only one-third of the gravity from earth. Will that be enough to maintain a healthy genome? Further experiments and space missions will show and I am very excited about it. We need to find a way to control the biological problems in space in order to become a multi-planetary species. But I am full of hope and excitement that humankind will find a way to the stars.

Ad Astra

Christoph Lahtz

About the author: The Biochemist and Epigenetics Dr. Christoph Lahtz started his career as a cancer scientist with a focus on ionizing radiation and its impact to the epigenome. He developed over the years a huge enthusiasm and interest for human space exploration. In these exciting times of the new space age, he decided to focus his future career on the biological problems of human space exploration and human settlements on helping to make humanity a multi-planetary species. One first step is the establishment of a nonprofit organization which is focused on space biology. Contact: clahtz [at] gmail.com. http://christophlahtz.com/

References:

1. Cheng JC, Matsen CB, Gonzales FA, Ye W, Greer S, Marquez VE, et al. Inhibition of DNA methylation and reactivation of silenced genes by zebularine. J Natl Cancer Inst 2003;95:399-409.

2. Hendrich B, Bird A. Identification, and characterization of a family of mammalian methyl-CpG binding proteins. Mol Cell Biol 1998;18:6538-47.

3. Zhu WG, Otterson GA. The interaction of histone deacetylase inhibitors and DNA methyltransferase inhibitors in the treatment of human cancer cells. Curr Med Chem Anticancer Agents 2003;3:187-99.

4. Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 2003;33 Suppl:245-54.

5. Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999;99:247-57.

6. Robertson KD, Wolffe AP. DNA methylation in health and disease. Nat Rev Genet 2000;1:11-9.

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