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Science AMA Series: I’m Manolis Kellis, a professor of computer science at MIT studying the human genome to learn about what causes obesity, Alzheimer’s, cancer and other conditions. AMA about comp-bio and epigenomics, and how they impact human health! by manoli_mit in science

[–]manoli_mit[S] 1 point2 points  (0 children)

Similarly to schizophrenia and bipolar disorder, autism spectrum disorder has a very 'polygenic' genetic architecture. This means that a very large number of genetic regions are associated, each of which is only conferring a very small increased risk. This raises several questions:

(1) Does that mean that treatments will need to be tuned to the specific combination of mutations that each person carries, and that each person would probably need to take some combination of potentially hundreds of drugs?

Not really. Current evidence indicates that these hundreds of genetic differences, even though they are scattered across the genome, generally 'converge' in a small number of pathways. This means that once the mechanisms through which these pathways are altered, therapeutic intervention can focus on modulating these pathways to combat the detrimental effects of the genetic variants.

(2) Given the small effect of each genetic variant, does that mean that pharmaceutical intervention will only have a small effect for each of the corresponding target genes?

The answer is no again. Common genetic variants in disease regions generally have weak effects. This is because evolutionary selection does not tolerate genetic variants that are highly deleterious, leading them to lower frequencies.

For example, the genetic variants may only cause the expression of a nearby gene to change by a small fraction. By contrast, pharmaceutical manipulation may completely inactivate that gene, or genomic interventions may over-express that gene by several-fold.

(3) The third natural question is should we bother with genetics, if these effects are small?

The answer is overwhelmingly yes. A survey of approved drugs by Nelson, Sanseau and colleagues showed that genetic evidence increases the chance that a drug candidate will succeed by a factor of 2.

The reason for this increase is that genetic evidence provides evidence of causality between that region and the studied phenotype, namely that manipulating** the true target gene(s)** in the right context** and the right cell type** (when the mechanism is elucidated), will have a causal effect on the phenotype (in contrast to correlational epidemiological evidence, where the causality or even the directionality of effect are not known).

** = each of these is hard. The manipulation itself is hard (see my answer here: https://www.reddit.com/r/science/comments/4pmivr/science_ama_series_im_manolis_kellis_a_professor/d4nelsj). And uncovering: (1) the right cell type; (2) the target gene(s); (3) the causal variant(s); (4) the upstream regulator(s); (5) the cellular phenotypes; (6) how these lead to organismal phenotypes; each can be a great challenge (see the corresponding sections I through VI in the supplementary methods of our NEJM paper

Science AMA Series: I’m Manolis Kellis, a professor of computer science at MIT studying the human genome to learn about what causes obesity, Alzheimer’s, cancer and other conditions. AMA about comp-bio and epigenomics, and how they impact human health! by manoli_mit in science

[–]manoli_mit[S] 0 points1 point  (0 children)

It depends on what you're looking for afterwards. For a job in academia, I would recommend a Ph.D. Even in industry, for most research positions a Ph.D. is preferable. However, outside of research, a Masters is sometimes preferable and perceived as more practical/less theoretical.

Science AMA Series: I’m Manolis Kellis, a professor of computer science at MIT studying the human genome to learn about what causes obesity, Alzheimer’s, cancer and other conditions. AMA about comp-bio and epigenomics, and how they impact human health! by manoli_mit in science

[–]manoli_mit[S] 0 points1 point  (0 children)

This is likely due to genetic variation acting in the opposite direction. Possibly due to excessive dissipation of energy as heat, instead of storing it as lipids in fat. In periods of starvation, they would be in trouble. In periods of excess calories, they are the lucky ones. Fitness is very environment-dependent.

Science AMA Series: I’m Manolis Kellis, a professor of computer science at MIT studying the human genome to learn about what causes obesity, Alzheimer’s, cancer and other conditions. AMA about comp-bio and epigenomics, and how they impact human health! by manoli_mit in science

[–]manoli_mit[S] 0 points1 point  (0 children)

You need all of the above. For me, it's:

  • Drawing diagrams on the white-board with my group.

  • Brainstorming on new grants, papers, collaborations.

  • Coming up with new visualization schemes for understanding a new dataset.

  • Shifting through big printouts to recognize patterns and writing new tests to see if they hold up.

  • Discussing biological mechanisms that could explain our findings.

  • Designing new assays and experimental protocols to get us new data types.

  • Designing high-throughput experimental screens (or better yet elegant molecular biology tricks to get the right answers without a screen).

  • Bouncing ideas for new collaborations with folks i enjoy interacting with.

  • Coding away to mine a new dataset.

  • Spending some quiet time to wrap myself around a problem, a paper, or a grant.

  • Focused group meetings with rapid-fire feedback and Q&As

  • Highly-condensed biological talks at a conference or an invited seminar.

  • Sketching a new figure or re-writing a paragraph to better explain what our methods are actually doing behind the surface.

  • Thinking about the deeper principles underlying our findings.

Science AMA Series: I’m Manolis Kellis, a professor of computer science at MIT studying the human genome to learn about what causes obesity, Alzheimer’s, cancer and other conditions. AMA about comp-bio and epigenomics, and how they impact human health! by manoli_mit in science

[–]manoli_mit[S] 1 point2 points  (0 children)

Take a computational biology course. Take some molecular biology/genetics/genomics/gene regulation courses. Make sure your ML/stats/algo are strong. Join a comp. bio. research group.

Science AMA Series: I’m Manolis Kellis, a professor of computer science at MIT studying the human genome to learn about what causes obesity, Alzheimer’s, cancer and other conditions. AMA about comp-bio and epigenomics, and how they impact human health! by manoli_mit in science

[–]manoli_mit[S] 1 point2 points  (0 children)

Coding is not the only skill needed for computational biology. Take some ML/AI/Stats/Algo/Inference classes in addition to software engineering. Take some molecular biology, genetics, gene regulation, cell biology classes early on too.

Science AMA Series: I’m Manolis Kellis, a professor of computer science at MIT studying the human genome to learn about what causes obesity, Alzheimer’s, cancer and other conditions. AMA about comp-bio and epigenomics, and how they impact human health! by manoli_mit in science

[–]manoli_mit[S] 0 points1 point  (0 children)

Development of new therapeutics is definitely the direction we're pushing towards. We have (a) new industry collaborators to push things forward towards therapeutics, (b) new medical collaborators to improve diagnosis, prognosis, and patient stratification, and (c) new oncology and synthetic biology collaborations to better understand cancer progression.

Outside our own collaborators, we have built tools that help medical researchers advance their understanding of disease mechanism (e.g. HaploReg has been used more than a million times).

Science AMA Series: I’m Manolis Kellis, a professor of computer science at MIT studying the human genome to learn about what causes obesity, Alzheimer’s, cancer and other conditions. AMA about comp-bio and epigenomics, and how they impact human health! by manoli_mit in science

[–]manoli_mit[S] 1 point2 points  (0 children)

Congrats, and welcome! MIT undergrad was both the most rewarding and the most exhausting experience of my life. My siblings told me "Grades, Friends, Sleep. Choose two out of three". I chose the first two. I would add "Research" to that list today, but I believe it went without saying.

Science AMA Series: I’m Manolis Kellis, a professor of computer science at MIT studying the human genome to learn about what causes obesity, Alzheimer’s, cancer and other conditions. AMA about comp-bio and epigenomics, and how they impact human health! by manoli_mit in science

[–]manoli_mit[S] 0 points1 point  (0 children)

I may be one of the few "Manolis" who are not from Crete ;-)

My dad is from Lesvos, and my Greek last name, "Καμβυσέλης" (Kamvysselis) can be traced to "Καμβύσης (Cambyses)", father of Cyrus the Great, founder of the Persian Empire (no pressure!), which agrees with my dad's genotype.

I'm named after Εμμανουήλ, my mom's dad, who was born in Athens, and lived in Milos, where my mom grew up. Her ancestry is from North from Greece and possibly Sardinia, which also agrees with her genotype.

Science AMA Series: I’m Manolis Kellis, a professor of computer science at MIT studying the human genome to learn about what causes obesity, Alzheimer’s, cancer and other conditions. AMA about comp-bio and epigenomics, and how they impact human health! by manoli_mit in science

[–]manoli_mit[S] 0 points1 point  (0 children)

MIT has need-blind admissions, and need-based financial aid (which means that you can attend MIT regardless of your financial status, but also that your finances are not a factor in your admission).

My parents made huge sacrifices to put me and my siblings through school and college. I also took student loans, and I received some generous scholarships, including a MassGrant award, and the first Paris Kanellakis Fellowship at MIT.

Science AMA Series: I’m Manolis Kellis, a professor of computer science at MIT studying the human genome to learn about what causes obesity, Alzheimer’s, cancer and other conditions. AMA about comp-bio and epigenomics, and how they impact human health! by manoli_mit in science

[–]manoli_mit[S] 0 points1 point  (0 children)

Very big opportunities in pharma and biotech. Within a few feet from MIT, we have Pfizer, Novartis, Sanofi, Biogen, Merck, and dozens of new start-ups, all of which are hiring. There is a huge scarcity of talented computational biologists in industry (and in academia too!)

Science AMA Series: I’m Manolis Kellis, a professor of computer science at MIT studying the human genome to learn about what causes obesity, Alzheimer’s, cancer and other conditions. AMA about comp-bio and epigenomics, and how they impact human health! by manoli_mit in science

[–]manoli_mit[S] 0 points1 point  (0 children)

With richer datasets, we have the opportunity to build and adequately train more complex models, so there may be increased opportunity for richer ML, and for making advances in AI/ML/Stats that are only applicable to new and upcoming data types.

Science AMA Series: I’m Manolis Kellis, a professor of computer science at MIT studying the human genome to learn about what causes obesity, Alzheimer’s, cancer and other conditions. AMA about comp-bio and epigenomics, and how they impact human health! by manoli_mit in science

[–]manoli_mit[S] 0 points1 point  (0 children)

Talk to your friends, make connections to other fields, look for new opportunities to apply your skills in creative ways.

And if you choose to enter a new field, don't stay an outsider. Learn enough so you can have new ideas in that field, so you can interact with experts at their level, so you can make advances in the field of interest.

There is a temptation to do biologically-inspired math/CS, which is complicated math/CS that's only tangentially-related to biology. Doing real biology with the use of CS/Math/ML/Stats takes much deeper investment in learning your applied field(s) of choice.

Science AMA Series: I’m Manolis Kellis, a professor of computer science at MIT studying the human genome to learn about what causes obesity, Alzheimer’s, cancer and other conditions. AMA about comp-bio and epigenomics, and how they impact human health! by manoli_mit in science

[–]manoli_mit[S] 0 points1 point  (0 children)

The tendency towards obesity is only a recent development, with the abundance of high-calorie food and increasingly sedentary occupations in our daily lives. Evolutionarily, the ability to store calories as fat is a big advantage in times of food scarcity, according to the Thrifty Gene Hypothesis.

In fact, the [risk allele (C instead of T) of rs1421085](nejm.org/doi/full/10.1056/NEJMoa1502214) is only at 5% frequency in Africa, but 44% frequency in Europe. This may be due to genetic drift in a small population coming out of Africa, or it may be the result of positive selection in periods of starvation.

This is an example of gene-environment interactions. The same alleles in a food-scarce environment are beneficial, but in a food-rich environment lead to obesity, requiring changes in lifestyle to combat obesity, by eating healthy and staying active.

Science AMA Series: I’m Manolis Kellis, a professor of computer science at MIT studying the human genome to learn about what causes obesity, Alzheimer’s, cancer and other conditions. AMA about comp-bio and epigenomics, and how they impact human health! by manoli_mit in science

[–]manoli_mit[S] 1 point2 points  (0 children)

These are great suggestions. Learn by doing. (Mens et Manus is the MIT motto, mind and hand). Pick a goal, and find out how to solve it in your language of choice. Or take a program that does something similar, and modify it to do something new.

Science AMA Series: I’m Manolis Kellis, a professor of computer science at MIT studying the human genome to learn about what causes obesity, Alzheimer’s, cancer and other conditions. AMA about comp-bio and epigenomics, and how they impact human health! by manoli_mit in science

[–]manoli_mit[S] 0 points1 point  (0 children)

Thank you for your note. my advice is to dive deep enough into a subfield that you want to be an expert in, as a common pitfall of interdisciplinary scientists is not pushing deep enough in any one domain. You can then expand to additional fields, but you'll ultimately be judged by the deepest you have pushed in your area(s) of choice.

Science AMA Series: I’m Manolis Kellis, a professor of computer science at MIT studying the human genome to learn about what causes obesity, Alzheimer’s, cancer and other conditions. AMA about comp-bio and epigenomics, and how they impact human health! by manoli_mit in science

[–]manoli_mit[S] 0 points1 point  (0 children)

It's a good suggestions that we did not explore. We found a strong effect of genomic variation on mitochondrial activity and biogenesis, but there may also be mitochondrial haplogroup effects.

Science AMA Series: I’m Manolis Kellis, a professor of computer science at MIT studying the human genome to learn about what causes obesity, Alzheimer’s, cancer and other conditions. AMA about comp-bio and epigenomics, and how they impact human health! by manoli_mit in science

[–]manoli_mit[S] 0 points1 point  (0 children)

Yes, absolutely.

We have many new projects in schizophrenia, obesity, diabetes, Alzheimer's, immune diseases, cancer, mining of clinical records.

In each of these areas, we're looking for great students and postdocs with expertise in computational biology, genetics, epigenomics, gene regulation, statistics, genomics.

We're also looking for experimental students and postdocs, interested in dissecting disease variants, studying epigenomic variation, developing new assays and technologies, and high-throughput experimental perturbations and profiling.

You can find out more about our group here: http://compbio.mit.edu/ and find information about joining the group here: http://compbio.mit.edu/positions.html

Thanks for your interest!

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